Monomaleimide-functionalized platinum compounds for cancer therapy

ABSTRACT

The present invention relates to novel monomaleimide-functionalized platinum compounds of formula (I), including in particular novel monomaleimide-functionalized oxaliplatin and carboplatin derivatives, as well as their use as medicaments, particularly for the treatment or prevention of cancer.

This application is a divisional of U.S. application Ser. No.16/060,559, filed Jun. 8, 2018, which is a national phase applicationunder 35 U.S.C. § 371 of International Application No.PCT/EP2016/080453, filed Dec. 9, 2016, which claims benefit of EuropeanApplication No. 15198739.3, filed Dec. 9, 2015, the entire contents ofeach of which are hereby incorporated by reference.

The present invention relates to novel monomaleimide-functionalizedplatinum compounds of formula (I), as described and defined hereinbelow, including in particular novel monomaleimide-functionalizedoxaliplatin and carboplatin derivatives, as well as their use asmedicaments, particularly for the treatment or prevention of cancer.

The application of platinum drugs in clinical cancer therapy roots in1969, when Rosenberg et al. discovered the promising anticancer activityof the platinum(II) complex cisplatin. The anticancer activity ofcisplatin is mainly based on the formation of platinum-DNA adducts,which leads to distortion of the helical DNA structure. This results inDNA strand breaks, inhibition of DNA replication and transcription, andas a final consequence cell cycle arrest and apoptosis. Based on itsvery strong anticancer activity, cisplatin or its successors carboplatinand oxaliplatin are nowadays an inherent part in nearly everychemotherapeutic scheme. Certain derivatives of such platinum drugs havealso been proposed, e.g., in: Abramkin, S. A. et al. J Med Chem. 2010;53(20):7356-64; Abramkin, S. et al. Dalton Trans. 2012; 41(10):3001-5;Abramkin, S., Dissertation 2012; and WO 2015/102922. However, treatmentwith platinum drugs is always accompanied (besides occurrence ofintrinsic or acquired resistance) by (severe) side effects, whichinclude besides nausea and vomiting, also nephrotoxicity orneurotoxicity. Consequently, there is significant interest in thedevelopment of new strategies to enhance tumor targeting (andconsequently to reduce side effects) of platinum drugs.

The anticancer activity of platinum(IV) complexes was discoveredtogether with cisplatin in the 1960s. So far, three platinum(IV) drugshave been tested in clinical trials: JM9 (iproplatin), tetraplatin(ormaplatin), and JM-216 (satraplatin). In general, platinum(IV)complexes are kinetically more inert than their platinum(II)counterparts and have consequently a lower reactivity with biomolecules.Probably due to their reduced cytotoxicity, platinum(IV) drugs have beenless extensively studied and developed than platinum(II) compounds.Nowadays, platinum(IV) complexes are considered as prodrugs, whichundergo reduction in the tumor tissue. During this process preferablythe axial ligands are released and the corresponding more activesquare-planar platinum(II) analogues are formed. Especially these axialligands are of paramount interest as they can be used for modulating arange of physicochemical and pharmacological properties such aslipophilicity, stability and reduction potential. Furthermore, theligands can be designed to target specific tumor sites or to attachadditional bioactive components.

Albumin is the most abundant plasma protein (35-50 g/L in human plasma)with a molecular weight of 66.5 kDa. Albumin has an average half-life of19 days and is, like most plasma proteins, synthesized in the liver. Thephysiological functions of albumin are multiple and diverse. Forexample, it is the major protein responsible for the colloid osmoticpressure of the blood. Most importantly with respect to drug delivery,albumin, a physiological carrier for several molecules such as bilirubinor metal ions, has very potent binding properties and is known to bindseveral therapeutic drugs (e.g. penicillins). Moreover, it is knownthat, due to the combination of leaky blood capillary with theabsence/defect of lymphatic drainage, albumin accumulates in malignanttissue (also called enhanced permeability and retention (EPR) effect).Consequently, strategies to enhance binding of drugs to serum albuminare an attractive and effective approach for targeted drug delivery intothe tumor tissue. Currently, there are several attempts to use thespecific tumor accumulation of albumin also for cytotoxic drugsespecially paclitaxel and doxorubicin. Thus, Abraxane®, an albuminpaclitaxel-containing nanoparticle, has been recently approved fornon-small cell lung cancer (NSCLC) as well as non-responding or relapsedbreast cancer and the maleimide-containing doxorubicin derivative(INNO-206, aldoxorubicin) is currently in phase Ill clinical trials.Consequently, the effectiveness and advantages of albumin as atumor-targeting strategy has already been proven in the clinicalsituation.

In a recent study (Pichler V et al. Chem Commun (Camb). 2013;49(22):2249-51), the first bismaleimide-containing, albumin-bindingplatinum(IV) drug KP2156 was synthesized together with the respectivesuccinimide derivative KP2157, which was found to possess no reactivitytowards albumin.

In particular, SEC-ICP-MS measurements using bovine blood serum provedspecific binding of KP2156 to the albumin-containing protein fraction,while KP2157 was exclusively detected in the low molecular weightfraction. To test the impact of albumin binding on the anticanceractivity of the new compounds in vivo the murine CT-26 colon cancermodel was used (the use of this syngeneic murine tumor model wasnecessary due to recently reported importance of the immune system forthe anticancer activity of oxaliplatin; Kroemer G et. al. Oncogene,2010, 29, 482-491; Jungwirth U et al. Mol Pharmacol. 2012;81(5):719-28). Both platinum complexes were well tolerated with nosignificant loss of body weight. However, in comparison to KP2157, thebismaleimide-functionalized derivative KP2156 displayed a significantlyhigher anticancer activity, resulting in a distinctly reduced mean tumorburden.

Interaction studies with albumin furthermore revealed that despite thepresence of two maleimide moieties, KP2156 is able to bind only to onealbumin molecule. The present inventors contemplated that the freesecond maleimide will result in unspecific reactions with other proteinsor thiol-containing molecules, and that this could lead to anuncontrolled behavior due to the occurrence of multiple metabolites invivo.

To address this issue, in the context of the present invention, thefirst mono-maleimide-functionalized oxaliplatin, cisplatin andcarboplatin derivatives were developed and tested for their anticanceractivity in vivo. This resulted in several completely unexpecteddiscoveries:

1) Although the albumin binding kinetic for the bismaleimide derivativesis in all cases 2-fold faster than for the monomaleimides, one of thenew oxaliplatin monomaleimide complexes as well as a carboplatinanalogue provided herein, i.e. KP2299 and KP2551, were found to bedistinctly more active than all other tested compounds (includingoxaliplatin, cisplatin and carboplatin), as also shown in FIGS. 1 and 2.

2) The monomaleimide compound KP2299 showed distinctly higher anticanceractivity than the structurally very similar monomaleimide compoundKP2260 (which has a methoxido group instead of the acetato group ofKP2299 at one axial position, as depicted below) and than KP2541 whichlacks the NH group in its linker, as also shown in FIGS. 1C and 1E. Inaddition, KP2299 exhibited highly increased aqueous solubility comparedto KP2260.

3) The cisplatin analogues of KP2299, namely KP2372 and KP2540, wereonly marginally active (see FIGS. 1D and E). This was highly surprisingas cisplatin derivatives usually possess similar or even higheranticancer activity.

4) In contrast to KP2372, KP2299 also exerted distinct anti-leukemicactivity (see FIG. 4 ). This was surprising as no EPR effect can beobserved in hematologic diseases (the accumulation of albumin can onlybe rationally explained for solid tumors).

The present invention thus solves the problem of providing novel andimproved platinum drugs for the therapeutic intervention in cancer,which show a considerably increased therapeutic effectiveness and afavorable side effect profile, particularly due to an advantageouslyenhanced tumor targeting.

Accordingly, the present invention provides a compound of the followingformula (I)

or a pharmaceutically acceptable salt or solvate thereof.

In formula (I), R¹ and R² are joined together to form a moiety (A1),(A2) or (A3):

R³ and R⁴ are joined together to form a moiety (1), or R³ is a moiety(B2) and R⁴ is —NH₃, or R³ and R⁴ are each —NH₃:

R⁵ is —N(R⁵¹)— or —CH₂—.

R⁵¹ is hydrogen or C₁₋₈ alkyl.

R⁶ is C₁₋₈ alkylene, wherein one or two —CH₂— units comprised in saidC₁₋₈ alkylene are each optionally replaced by a group independentlyselected from —O—, —CO—, —C(═O)O—, —O—C(═O)—, —N(R⁶¹)—, —N(R⁶¹)—CO—,—CO—N(R⁶¹)—, arylene, and heteroarylene, wherein said arylene and saidheteroarylene are each optionally substituted with one or more groupsR⁶².

Each R⁶¹ is independently selected from hydrogen and C₁₋₈ alkyl.

Each R⁶² is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —(C₀₋₃ alkylene)-OH, —(C₀₋₃ alkylene)-O(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SH, —(C₀₋₃ alkylene)-S(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH₂,—(C₀₋₃ alkylene)-NH(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)(C₁₋₈alkyl), —(C₀₋₃ alkylene)-halogen, —(C₀₋₃ alkylene)-(C₁₋₈ haloalkyl),—(C₀₋₃ alkylene)-CF₃, —(C₀₋₃ alkylene)-CN, —(C₀₋₃ alkylene)-CHO, —(C₀₋₃alkylene)-CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-COOH, —(C₀₋₃alkylene)-CO—O—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-O—CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—NH₂, —(C₀₋₃ alkylene)-CO—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—CO—(C₁₋₈alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—NH₂, —(C₀₋₃ alkylene)-SO₂—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—SO₂—(C₁₋₈alkyl), and —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-SO₂—(C₁₋₈ alkyl).

R⁷ is selected from hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —O—(C₁₋₈ alkyl),—O—(C₂₋₈ alkenyl), —O—(C₂₋₈ alkynyl), —O— cycloalkyl,—O-heterocycloalkyl, —O-aryl, —O-heteroaryl, —N(R⁷¹)—(C₁₋₈ alkyl),—N(R⁷¹)—(C₂₋₈ alkenyl), —N(R⁷¹)—(C₂₋₈ alkynyl), —N(R⁷¹)-cycloalkyl,—N(R⁷¹)-heterocycloalkyl, —N(R⁷¹)-aryl, and —N(R⁷¹)-heteroaryl, whereinsaid C₁₋₈ alkyl or the C₁₋₈ alkyl moiety comprised in any of theaforementioned groups, said C₂₋₈ alkenyl or the C₂₋₈ alkenyl moietycomprised in any of the aforementioned groups, and said C₂₋₈ alkynyl orthe C₂₋₈ alkynyl moiety comprised in any of the aforementioned groupsare each optionally substituted with one or more groups R⁷², and furtherwherein said cycloalkyl or the cycloalkyl moiety comprised in any of theaforementioned groups, said heterocycloalkyl or the heterocycloalkylmoiety comprised in any of the aforementioned groups, said aryl or thearyl moiety comprised in any of the aforementioned groups, and saidheteroaryl or the heteroaryl moiety comprised in any of theaforementioned groups are each optionally substituted with one or moregroups R⁷³.

Each R⁷¹ is independently selected from hydrogen and C₁₋₈ alkyl.

Each R⁷² is independently selected from —OH, —O(C₁₋₈ alkyl), —SH,—S(C₁₋₈ alkyl), —NH₂, —NH(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl),halogen, C₁₋₈ haloalkyl, —CF₃, —CN, —CHO, —CO—(C₁₋₈ alkyl), —COOH,—CO—O—(C₁₋₈ alkyl), —O—CO—(C₁₋₈ alkyl), —CO—NH₂, —CO—NH(C₁₋₈ alkyl),—CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—CO—(C₁₋₈ alkyl), —N(C₁₋₈alkyl)-CO—(C₁₋₈ alkyl), —SO₂—NH₂, —SO₂—NH(C₁₋₈ alkyl), —SO₂—N(C₁₋₈alkyl)(C₁₋₈ alkyl), —NH—SO₂—(C₁₋₈ alkyl), and —N(C₁₋₈ alkyl)-SO₂—(C₁₋₈alkyl).

Each R⁷³ is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —(C₀₋₃ alkylene)-OH, —(C₀₋₃ alkylene)-O(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SH, —(C₀₋₃ alkylene)-S(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH₂,—(C₀₋₃ alkylene)-NH(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)(C₁₋₈alkyl), —(C₀₋₃ alkylene)-halogen, —(C₀₋₃ alkylene)-(C₁₋₈ haloalkyl),—(C₀₋₃ alkylene)-CF₃, —(C₀₋₃ alkylene)-CN, —(C₀₋₃ alkylene)-CHO, —(C₀₋₃alkylene)-CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-COOH, —(C₀₋₃alkylene)-CO—O—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-O—CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—NH₂, —(C₀₋₃ alkylene)-CO—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—CO—(C₁₋₈alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—NH₂, —(C₀₋₃ alkylene)-SO₂—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—SO₂—(C₁₋₈alkyl), and —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-SO₂—(C₁₋₈ alkyl).

Each R⁸ is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —OH, —O—(C₁₋₈ alkyl), —SH, —S—(C₁₋₈ alkyl), —NH₂, —NH(C₁₋₈alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl), halogen, C₁₋₈ haloalkyl, —CF₃, —CN,—CHO, —CO—(C₁₋₈ alkyl), —COOH, —CO—O—(C₁₋₈ alkyl), —O—CO—(C₁₋₈ alkyl),—CO—NH₂, —CO—NH(C₁₋₈ alkyl), —CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—CO—(C₁₋₈alkyl), —N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —SO₂—NH₂, —SO₂—NH(C₁₋₈ alkyl),—SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—SO₂—(C₁₋₈ alkyl), and —N(C₁₋₈alkyl)-SO₂—(C₁₋₈ alkyl).

Each R⁹ is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —OH, —O—(C₁₋₈ alkyl), —SH, —S—(C₁₋₈ alkyl), —NH₂, —NH(C₁₋₈alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl), halogen, C₁₋₈ haloalkyl, —CF₃, —CN,—CHO, —CO—(C₁₋₈ alkyl), —COOH, —CO—O—(C₁₋₈ alkyl), —O—CO—(C₁₋₈ alkyl),—CO—NH₂, —CO—NH(C₁₋₈ alkyl), —CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—CO—(C₁₋₈alkyl), —N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —SO₂—NH₂, —SO₂—NH(C₁₋₈ alkyl),—SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—SO₂—(C₁₋₈ alkyl), and —N(C₁₋₈alkyl)-SO₂—(C₁₋₈ alkyl).

n is an integer of 0 to 8.

m is an integer of 0 to 6.

The present invention also relates to a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof, in combination with a pharmaceuticallyacceptable excipient. Accordingly, the invention relates to a compoundof formula (I) or a pharmaceutically acceptable salt or solvate thereof,or a pharmaceutical composition comprising any of the aforementionedentities and a pharmaceutically acceptable excipient, for use as amedicament.

The invention further relates to a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition comprising any of the aforementioned entities and apharmaceutically acceptable excipient, for use in the treatment orprevention of cancer.

Moreover, the present invention relates to the use of a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof inthe preparation of a medicament for the treatment or prevention ofcancer.

The invention likewise relates to a method of treating or preventingcancer, the method comprising administering a compound of formula (I) ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition comprising any of the aforementioned entitiesin combination with a pharmaceutically acceptable excipient, to asubject (preferably a human) in need thereof.

It will be understood that a therapeutically effective amount of thecompound of formula (I) or the pharmaceutically acceptable salt orsolvate thereof, or of the pharmaceutical composition, is to beadministered in accordance with this method.

The cancer to be treated or prevented in accordance with the presentinvention is preferably selected from gastrointestinal cancer,colorectal cancer (e.g., McLean et al. or Goldenstein et al. both ClinColorectal Cancer. 2015), colon cancer, liver cancer (e.g.,hepatocellular carcinoma), pancreatic cancer (e.g., Cid-Arregui et al.World J Gastroenterol. 2015), biliary tract cancer (e.g., Yang R et al.Anticancer Drugs 2013), stomach cancer, genitourinary cancer, bladdercancer, testicular cancer, cervical cancer, malignant mesothelioma,osteogenic sarcoma, esophageal cancer, laryngeal cancer, prostate cancer(e.g., hormone-refractory prostate cancer), lung cancer (e.g., smallcell lung cancer or non-small cell lung cancer), breast cancer (e.g.,triple-negative breast cancer, or breast cancer having a BRCA1 and/orBRCA2 gene mutation), hematological cancer, leukemia (e.g., acutelymphoblastic leukemia, acute myeloid leukemia, chronic lymphocyticleukemia, or chronic myeloid leukemia), lymphoma (e.g., Hodgkin lymphomaor non-Hodgkin lymphoma, such as, e.g., follicular lymphoma or diffuselarge B-cell lymphoma), ovarian cancer (e.g., Bogliolo et al. ExpertOpin Investig Drugs. 2015), brain cancer, neuroblastoma, Ewing'ssarcoma, kidney cancer, epidermoid cancer, skin cancer, melanoma, headand/or neck cancer (e.g., head and neck squamous cell carcinoma), andmouth cancer. The cancer to be treated or prevented in accordance withthe invention may also be a gynecological cancer, such as, e.g.,cervical cancer, ovarian cancer (e.g., ovarian carcinoma), uterinecancer, vaginal cancer, or vulvar cancer, particularly endometrialcancer. The cancer to be treated or prevented may further be, e.g.,hepatobiliary cancer, thymoma, Merkel-cell cancer, anal cancer(particularly anal squamous cell carcinoma), or a neuroendocrine cancer.The present invention relates, in particular, to the treatment orprevention of colorectal cancer, colon cancer, pancreatic cancer, lungcancer (particularly non-small cell lung cancer), ovarian cancer(particularly ovarian carcinoma), bladder cancer, cervical cancer,malignant mesothelioma, melanoma, head and/or neck cancer (particularlyhead and neck squamous cell carcinoma), or testicular cancer. Even morepreferably, the cancer to be treated or prevented in accordance with thepresent invention is colorectal cancer, colon cancer, pancreatic cancer,lung cancer (particularly non-small cell lung cancer), ovarian cancer(particularly ovarian carcinoma), cervical cancer, melanoma, or headand/or neck cancer (particularly head and neck squamous cell carcinoma).Accordingly, the cancer to be treated or prevented may thus be, forexample, ovarian cancer (particularly ovarian carcinoma), lung cancer(particularly non-small cell lung cancer), or head and/or neck cancer(particularly head and neck squamous cell carcinoma). Yet even morepreferably, the cancer to be treated or prevented in accordance with thepresent invention is colorectal cancer, colon cancer, or pancreaticcancer.

The compounds of formula (I) will be described in more detail in thefollowing:

or a pharmaceutically acceptable salt or solvate thereof.

In formula (I), R¹ and R² are joined together to form a moiety (A1),(A2) or (A3):

Preferably, R¹ and R² are joined together to form a moiety (A1) or (A2).More preferably, R¹ and R² are joined together to form a moiety (A1).

R³ and R⁴ are joined together to form a moiety (1), or R³ is a moiety(B2) and R⁴ is —NH₃, or R³ and R⁴ are each —NH₃:

Preferably, R³ and R⁴ are joined together to form a moiety (1), or R³and R⁴ are each —NH₃. More preferably, R³ and R⁴ are joined together toform a moiety (1).

It is preferred that R¹, R², R³ and R⁴ are selected so as to provide acompound of formula (I) having any one of the following structures:

It is particularly preferred that either R¹ and R² are joined togetherto form a moiety (A1) and R³ and R⁴ are joined together to form a moiety(B31), or R¹ and R² are joined together to form a moiety (A2) and R³ andR⁴ are each —NH₃. Most preferably, R¹ and R² are joined together to forma moiety (A1) and R³ and R⁴ are joined together to form a moiety (B31).

It is furthermore preferred that the two asymmetric carbon atoms of thecyclohexyl ring comprised in moiety (E1) both have the R-configuration,i.e. that the cyclohexane-1,2-diamine group in moiety (E1) is present as(1R,2R)-cyclohexane-1,2-diamine, as illustrated in the following:

R⁵ is —N(R⁵¹)— or —CH₂—. Preferably, R⁵ is —N(R⁵¹)—.

R⁵¹ is hydrogen or C₁₋₈ alkyl. Preferably, R⁵¹ is hydrogen or C₁₋₅alkyl. More preferably, R⁵¹ is hydrogen, methyl, or ethyl. Even morepreferably, R⁵¹ is hydrogen.

In accordance with the meanings of R⁵ and R⁵¹ described above, it isparticularly preferred that R⁵ is —NH—, —N(—CH₃)— or —N(—CH₂CH₃)—, andmost preferably R⁵ is —NH—.

R⁶ is C₁₋₈ alkylene, wherein one or two —CH₂— units comprised in saidC₁₋₈ alkylene are each optionally replaced by a group independentlyselected from —O—, —CO—, —C(═O)O—, —O—C(═O)—, —N(R⁶¹)—, —N(R⁶¹)—CO—,—CO—N(R⁶¹)—, arylene, and heteroarylene, wherein said arylene and saidheteroarylene are each optionally substituted with one or more (e.g.,one, two, three, or four) groups R⁶². Preferably, R⁶ is C₁₋₈ alkylene,wherein one or two —CH₂— units comprised in said C₁₋₈ alkylene are eachoptionally replaced by a group independently selected from —O—, —CO—,—C(═O)O—, —O—C(═O)—, —N(R⁶¹)—, —N(R⁶¹)—CO—, and —CO—N(R⁶¹)—. Morepreferably, R⁶ is C₁₋₈ alkylene, wherein one —CH₂— unit comprised insaid C₁₋₈ alkylene is optionally replaced by a group selected from —O—,—CO—, —C(═O)O—, —O—C(═O)—, —N(R⁶¹)—, —N(R⁶¹)—CO—, and —CO—N(R⁶¹)—. Evenmore preferably, R⁶ is C₁₋₈ alkylene (such as, e.g., —CH₂—, —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)—, —(CH₂)₆—, —(CH₂)₇—, or —(CH₂)₈—). Even morepreferably, R⁶ is C₁₋₅ alkylene. Yet even more preferably, R⁶ isselected from —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, and —(CH₂)—. Stillmore preferably, R⁶ is selected from —CH₂—, —(CH₂)₂—, and —(CH₂)₃—. Mostpreferably, R⁶ is —(CH₂)₂—.

Each R⁶¹ is independently selected from hydrogen and C₁₋₈ alkyl.Preferably, each R⁶¹ is independently selected from hydrogen and C₁₋₅alkyl. More preferably, each R⁶¹ is independently selected fromhydrogen, methyl, and ethyl. Even more preferably, each R⁶¹ is hydrogen.

Each R⁶² is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —(C₀₋₃ alkylene)-OH, —(C₀₋₃ alkylene)-O(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SH, —(C₀₋₃ alkylene)-S(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH₂,—(C₀₋₃ alkylene)-NH(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)(C₁₋₈alkyl), —(C₀₋₃ alkylene)-halogen, —(C₀₋₃ alkylene)-(C₁₋₈ haloalkyl),—(C₀₋₃ alkylene)-CF₃, —(C₀₋₃ alkylene)-CN, —(C₀₋₃ alkylene)-CHO, —(C₀₋₃alkylene)-CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-COOH, —(C₀₋₃alkylene)-CO—O—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-O—CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—NH₂, —(C₀₋₃ alkylene)-CO—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—CO—(C₁₋₈alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—NH₂, —(C₀₋₃ alkylene)-SO₂—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—SO₂—(C₁₋₈alkyl), and —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-SO₂—(C₁₋₈ alkyl). Preferably,each R⁶² is independently selected from C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅alkynyl, —OH, —O(C₁₋₅ alkyl), —SH, —S(C₁₋₅ alkyl), —NH₂, —NH(C₁₋₅alkyl), —N(C₁₋₅ alkyl)(C₁₋₅ alkyl), halogen, C₁₋₅ haloalkyl, —CF₃, —CN,—CHO, —CO—(C₁₋₅ alkyl), —COOH, —CO—O—(C₁₋₅ alkyl), —O—CO—(C₁₋₅ alkyl),—CO—NH₂, —CO—NH(C₁₋₅ alkyl), —CO—N(C₁₋₅ alkyl)(C₁₋₅ alkyl), —NH—CO—(C₁₋₅alkyl), —N(C₁₋₅ alkyl)-CO—(C₁₋₅ alkyl), —SO₂—NH₂, —SO₂—NH(C₁₋₅ alkyl),—SO₂—N(C₁₋₅ alkyl)(C₁₋₅ alkyl), —NH—SO₂—(C₁₋₅ alkyl), and —N(C₁₋₅alkyl)-SO₂—(C₁₋₅ alkyl). More preferably, each R⁶² is independentlyselected from C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, —OH, —O(C₁₋₅alkyl), —SH, —S(C₁₋₅ alkyl), —NH₂, —NH(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)(C₁₋₅alkyl), halogen, C₁₋₅ haloalkyl, —CF₃, and —CN. Even more preferably,each R⁶² is independently selected from C₁₋₄ alkyl (e.g., methyl orethyl), —OH, —O(C₁₋₄ alkyl) (e.g., —OCH₃ or —OCH₂CH₃), —NH₂, —NH(C₁₋₄alkyl) (e.g., —NHCH₃), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl) (e.g., —N(CH₃)₂),halogen (e.g., —F, —Cl, —Br, or —I), —CF₃, and —CN.

R⁷ is selected from hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —O—(C₁₋₈ alkyl),—O—(C₂₋₈ alkenyl), —O—(C₂₋₈ alkynyl), —O-cycloalkyl,—O-heterocycloalkyl, —O-aryl, —O-heteroaryl, —N(R⁷¹)—(C₁₋₈ alkyl),—N(R⁷¹)—(C₂₋₈ alkenyl), —N(R⁷¹)—(C₂₋₈ alkynyl), —N(R⁷¹)-cycloalkyl,—N(R⁷¹)-heterocycloalkyl, —N(R⁷¹)-aryl, and —N(R⁷¹)-heteroaryl, whereinsaid C₁₋₈ alkyl or the C₁₋₈ alkyl moiety comprised in any of theaforementioned groups (e.g., the C₁₋₈ alkyl moiety comprised in said—O—(C₁₋₈ alkyl)), said C₂₋₈ alkenyl or the C₂₋₈ alkenyl moiety comprisedin any of the aforementioned groups, and said C₂₋₈ alkynyl or the C₂₋₈alkynyl moiety comprised in any of the aforementioned groups are eachoptionally substituted with one or more (e.g., one, two, or three)groups R⁷², and further wherein said cycloalkyl or the cycloalkyl moietycomprised in any of the aforementioned groups (e.g., the cycloalkylmoiety comprised in said —O-cycloalkyl), said heterocycloalkyl or theheterocycloalkyl moiety comprised in any of the aforementioned groups,said aryl or the aryl moiety comprised in any of the aforementionedgroups, and said heteroaryl or the heteroaryl moiety comprised in any ofthe aforementioned groups are each optionally substituted with one ormore (e.g., one, two, three, or four) groups R⁷³. Preferably, R⁷ isselected from hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,cycloalkyl, heterocycloalkyl, aryl (e.g., phenyl), heteroaryl, —O—(C₁₋₈alkyl), —O—(C₂₋₈ alkenyl), —O—(C₂₋₈ alkynyl), —O-cycloalkyl,—O-heterocycloalkyl, —O-aryl, and —O-heteroaryl, wherein said C₁₋₈alkyl, said C₂₋₈ alkenyl, said C₂₋₈ alkynyl, the C₁₋₈ alkyl moietycomprised in said —O—(C₁₋₈ alkyl), the C₂₋₈ alkenyl moiety comprised insaid —O—(C₂₋₈ alkenyl), and the C₂₋₈ alkynyl moiety comprised in said—O—(C₂₋₈ alkynyl) are each optionally substituted with one or more(e.g., one, two, or three) groups R⁷², and further wherein saidcycloalkyl, said heterocycloalkyl, said aryl, said heteroaryl, thecycloalkyl moiety comprised in said —O-cycloalkyl, the heterocycloalkylmoiety comprised in said —O-heterocycloalkyl, the aryl moiety comprisedin said —O-aryl, and the heteroaryl moiety comprised in said—O-heteroaryl are each optionally substituted with one or more (e.g.,one, two, three, or four) groups R⁷³. More preferably, R⁷ is selectedfrom C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl. Even more preferably,R⁷ is C₁₋₈ alkyl. Yet even more preferably, R⁷ is C₁₋₅ alkyl. Still morepreferably, R⁷ is selected from —CH₃, —CH₂CH₃, —(CH₂)₂—CH₃, —(CH₂)₃—CH₃,and —(CH₂)₄—CH₃. Most preferably, R⁷ is —CH₃.

Each R⁷¹ is independently selected from hydrogen and C₁₋₈ alkyl.Preferably, each R⁷¹ is independently selected from hydrogen and C₁₋₅alkyl. More preferably, each R⁷¹ is independently selected fromhydrogen, methyl, and ethyl. Even more preferably, each R⁷¹ is hydrogen.

Each R⁷² is independently selected from —OH, —O(C₁₋₈ alkyl), —SH,—S(C₁₋₈ alkyl), —NH₂, —NH(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl),halogen, C₁₋₈ haloalkyl, —CF₃, —CN, —CHO, —CO—(C₁₋₈ alkyl), —COOH,—CO—O—(C₁₋₈ alkyl), —O—CO—(C₁₋₈ alkyl), —CO—NH₂, —CO—NH(C₁₋₈ alkyl),—CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—CO—(C₁₋₈ alkyl), —N(C₁₋₈alkyl)-CO—(C₁₋₈ alkyl), —SO₂—NH₂, —SO₂—NH(C₁₋₈ alkyl), —SO₂—N(C₁₋₈alkyl)(C₁₋₈ alkyl), —NH—SO₂—(C₁₋₈ alkyl), and —N(C₁₋₈ alkyl)-SO₂—(C₁₋₈alkyl). Preferably, each R⁷² is independently selected from —OH, —O(C₁₋₅alkyl), —SH, —S(C₁₋₅ alkyl), —NH₂, —NH(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)(C₁₋₅alkyl), halogen, C₁₋₅ haloalkyl, —CF₃, and —CN. More preferably, eachR⁷² is independently selected from C₁₋₄ alkyl (e.g., methyl or ethyl),—OH, —O(C₁₋₄ alkyl) (e.g., —OCH₃ or —OCH₂CH₃), —NH₂, —NH(C₁₋₄ alkyl)(e.g., —NHCH₃), —N(C₄ alkyl)(C₁₋₄ alkyl) (e.g., —N(CH₃)₂), halogen(e.g., —F, —Cl, —Br, or —I), —CF₃, and —CN.

Each R⁷³ is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —(C₀₋₃ alkylene)-OH, —(C₀₋₃ alkylene)-O(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SH, —(C₀₋₃ alkylene)-S(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH₂,—(C₀₋₃ alkylene)-NH(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)(C₁₋₈alkyl), —(C₀₋₃ alkylene)-halogen, —(C₀₋₃ alkylene)-(C₁₋₈ haloalkyl),—(C₀₋₃ alkylene)-CF₃, —(C₀₋₃ alkylene)-CN, —(C₀₋₃ alkylene)-CHO, —(C₀₋₃alkylene)-CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-COOH, —(C₀₋₃alkylene)-CO—O—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-O—CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—NH₂, —(C₀₋₃ alkylene)-CO—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—CO—(C₁₋₈alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—NH₂, —(C₀₋₃ alkylene)-SO₂—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—SO₂—(C₁₋₈alkyl), and —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-SO₂—(C₁₋₈ alkyl). Preferably,each R⁷³ is independently selected from C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅alkynyl, —OH, —O(C₁₋₅ alkyl), —SH, —S(C₁₋₅ alkyl), —NH₂, —NH(C₁₋₅alkyl), —N(C₁₋₅ alkyl)(C₁₋₅ alkyl), halogen, C₁₋₅ haloalkyl, —CF₃, —CN,—CHO, —CO—(C₁₋₅ alkyl), —COOH, —CO—O—(C₁₋₅ alkyl), —O—CO—(C₁₋₅ alkyl),—CO—NH₂, —CO—NH(C₁₋₅ alkyl), —CO—N(C₁₋₅ alkyl)(C₁₋₅ alkyl), —NH—CO—(C₁₋₅alkyl), —N(C₁₋₅ alkyl)-CO—(C₁₋₅ alkyl), —SO₂—NH₂, —SO₂—NH(C₁₋₅ alkyl),—SO₂—N(C₁₋₅ alkyl)(C₁₋₅ alkyl), —NH—SO₂—(C₁₋₅ alkyl), and —N(C₁₋₅alkyl)-SO₂—(C₁₋₅ alkyl). More preferably, each R⁷³ is independentlyselected from C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, —OH, —O(C₁₋₅alkyl), —SH, —S(C₁₋₅ alkyl), —NH₂, —NH(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)(C₁₋₅alkyl), halogen, C₁₋₅ haloalkyl, —CF₃, and —CN. Even more preferably,each R⁷³ is independently selected from C₁₋₄ alkyl (e.g., methyl orethyl), —OH, —O(C₁₋₄ alkyl) (e.g., —OCH₃ or —OCH₂CH₃), —NH₂, —NH(C₁₋₄alkyl) (e.g., —NHCH₃), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl) (e.g., —N(CH₃)₂),halogen (e.g., —F, —C, —Br, or —I), —CF₃, and —CN.

Each R⁸ is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —OH, —O—(C₁₋₈ alkyl), —SH, —S—(C₁₋₈ alkyl), —NH₂, —NH(C₁₋₈alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl), halogen, C₁₋₈ haloalkyl, —CF₃, —CN,—CHO, —CO—(C₁₋₈ alkyl), —COOH, —CO—O—(C₁₋₈ alkyl), —O—CO—(C₁₋₈ alkyl),—CO—NH₂, —CO—NH(C₁₋₈ alkyl), —CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—CO—(C₁₋₈alkyl), —N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —SO₂—NH₂, —SO₂—NH(C₁₋₈ alkyl),—SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—SO₂—(C₁₋₈ alkyl), and —N(C₁₋₈alkyl)-SO₂—(C₁₋₈ alkyl). Preferably, each R⁸ is independently selectedfrom C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl. More preferably, eachR⁸ is independently C₁₋₈ alkyl. Even more preferably, each R⁸ isindependently C₁₋₄ alkyl (e.g., methyl or ethyl).

For example, the moiety (1) may carry one methyl substituent (i.e., n is1, and R⁸ is methyl), particularly in the 4-position of the cyclohexylring, as shown in the following:

Any substituent R⁸, if present, may have the R-configuration or theS-configuration. For example, if the moiety (E1) carries one methylsubstituent, particularly in the 4-position of the cyclohexyl ring (asdescribed above), this methyl substituent may have the R-configurationor the S-configuration. Thus, moiety (E1) may be, e.g., a(1R,2R,4R)-4-methyl-cyclohexane-1,2-diamine moiety or a(1R,2R,4S)-4-methyl-cyclohexane-1,2-diamine moiety.

Each R⁹ is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —OH, —O—(C₁₋₈ alkyl), —SH, —S—(C₁₋₈ alkyl), —NH₂, —NH(C₁₋₈alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl), halogen, C₁₋₈ haloalkyl, —CF₃, —CN,—CHO, —CO—(C₁₋₈ alkyl), —COOH, —CO—O—(C₁₋₈ alkyl), —O—CO—(C₁₋₈ alkyl),—CO—NH₂, —CO—NH(C₁₋₈ alkyl), —CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—CO—(C₁₋₈alkyl), —N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —SO₂—NH₂, —SO₂—NH(C₁₋₈ alkyl),—SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—SO₂—(C₁₋₈ alkyl), and —N(C₁₋₈alkyl)-SO₂—(C₁₋₈ alkyl). Preferably, each R⁹ is independently selectedfrom C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl. More preferably, eachR⁹ is independently C₁₋₈ alkyl. Even more preferably, each R⁹ isindependently C₁₋₄ alkyl (e.g., methyl or ethyl).

n is an integer of 0 to 8. Preferably, n is an integer of 0 to 6. Morepreferably, n is 0, 1, 2, 3, or 4. Even more preferably, n is 0, 1, or2. Yet even more preferably, n is 0 or 1. Most preferably, n is 0.

m is an integer of 0 to 6. More preferably, m is 0, 1, 2, 3, or 4. Evenmore preferably, m is 0, 1, or 2. Yet even more preferably, m is 0 or 1.Most preferably, m is 0.

It is to be understood that n indicates the number of substituents R⁸that are bound to the corresponding cyclohexyl ring, e.g., thecyclohexyl ring comprised in moiety (1) or (B2) or in formula (Ia). If nis 0, then this cyclohexyl ring is not substituted with any group R⁸,i.e. is substituted with hydrogen instead of R⁸. Likewise, it is to beunderstood that m indicates the number of substituents R⁹ that are boundto the cyclobutyl ring comprised in moiety (A2). If m is 0, then thiscyclobutyl ring is unsubstituted, i.e. is substituted with hydrogeninstead of R⁹.

Exemplary compounds of formula (I) are the following compounds KP2299,17, 18, 19, 20, 21, 22, 23, 24, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41 and 42 as well as pharmaceutically acceptable salts or solvates ofany of these compounds:

In a particularly preferred embodiment, the compound of formula (I) is acompound of the following formula (Ia) or a pharmaceutically acceptablesalt or solvate thereof:

wherein the groups and variables in formula (Ia), including inparticular R⁵, R⁶, R⁷, R⁸ and n, have the same meanings, including thesame preferred meanings, as described and defined herein above for thecompound of formula (I).

In an even more preferred embodiment, the compound of formula (I) is acompound of the following formula (Ib) or a pharmaceutically acceptablesalt or solvate thereof:

In formula (Ib), R⁷⁴ is selected from hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,—O—(C₁₋₈ alkyl), —O—(C₂₋₈ alkenyl), —O—(C₂₋₈ alkynyl), —O-cycloalkyl,—O-heterocycloalkyl, —O-aryl, and —O-heteroaryl, wherein said C₁₋₈alkyl, said C₂₋₈ alkenyl, said C₂₋₈ alkynyl, the C₁₋₈ alkyl moietycomprised in said —O—(C₁₋₈ alkyl), the C₂₋₈ alkenyl moiety comprised insaid —O—(C₂₋₈ alkenyl), and the C₂₋₈ alkynyl moiety comprised in said—O—(C₂₋₈ alkynyl) are each optionally substituted with one or more(e.g., one, two, or three) groups R⁷², and further wherein saidcycloalkyl, said heterocycloalkyl, said aryl, said heteroaryl, thecycloalkyl moiety comprised in said —O-cycloalkyl, the heterocycloalkylmoiety comprised in said —O-heterocycloalkyl, the aryl moiety comprisedin said —O-aryl, and the heteroaryl moiety comprised in said—O-heteroaryl are each optionally substituted with one or more (e.g.,one, two, three, or four) groups R⁷³. The groups R⁷² and R⁷³ have thesame meanings, including the same preferred meanings, as described anddefined herein above for the compound of formula (I).

Preferably, R⁷⁴ is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₂₋₈alkynyl. More preferably, R⁷⁴ is C₁₋₈ alkyl. Even more preferably, R⁷⁴is C₁₋₅ alkyl. Yet even more preferably, R⁷⁴ is selected from —CH₃,—CH₂CH₃, —(CH₂)₂—CH₃, —(CH₂)₃—CH₃, and —(CH₂)₄—CH₃. Most preferably, R⁷⁴is —CH₃.

p is an integer of 1 to 8. Preferably, p is 1, 2, 3, 4, or 5. Morepreferably, p is 1, 2, or 3. Even more preferably, p is 2.

A particularly preferred compound of formula (I), (Ia) or (Ib) is thefollowing compound (which is also referred as “KP2299” in thisspecification):

or a pharmaceutically acceptable salt or solvate thereof.

In a further specific embodiment, the compound of formula (I) is acompound of the following formula (Ic) or a pharmaceutically acceptablesalt or solvate thereof:

wherein the groups R¹ and R² in formula (Ic) are joined together to forma moiety (A1) or (A2) as defined herein above, preferably a moiety (A2),and wherein the further groups and variables in formula (Ic), includingin particular R⁵, R⁶, R⁷, R⁹ and m, have the same meanings, includingthe same preferred meanings, as described and defined herein above forthe compound of formula (I).

Exemplary compounds of formula (Ic) are the following compounds 17, 20,31, 32, 37 and 38 as well as pharmaceutically acceptable salts orsolvates of any of these compounds:

In a further preferred embodiment, the compound of formula (I) is acompound of the following formula (Id) or a pharmaceutically acceptablesalt or solvate thereof:

wherein the groups and variables in formula (Id), including inparticular R⁵, R⁶, R⁷, R⁹ and m, have the same meanings, including thesame preferred meanings, as described and defined herein above for thecompound of formula (I).

Particularly preferred compounds of formula (Id) are the followingcompounds 20 and 31 as well as pharmaceutically acceptable salts orsolvates of any of these compounds:

In a further embodiment, the compound of formula (I) is a compound ofthe following formula (Ie) or a pharmaceutically acceptable salt orsolvate thereof:

wherein R¹ and R² in formula (Ie) are joined together to form a moiety(A2) or (A3) as defined herein above, and wherein the further groups andvariables in formula (Ie) have the same meanings, including the samepreferred meanings, as described and defined herein above for thecompound of formula (I).

In a further embodiment, the compound of formula (I) is a compound ofthe following formula (If) or a pharmaceutically acceptable salt orsolvate thereof:

wherein R¹ and R² in formula (If) are joined together to form a moiety(A2) as defined herein above, and wherein the further groups andvariables in formula (If) have the same meanings, including the samepreferred meanings, as described and defined herein above for thecompound of formula (I).

In a further embodiment, the compound of formula (I) is a compound ofthe following formula (Ig) or a pharmaceutically acceptable salt orsolvate thereof:

wherein R¹ and R² in formula (Ig) are joined together to form a moiety(A2) as defined herein above, wherein R³ and R⁴ are joined together toform a moiety (E1) as defined herein above, and wherein the furthergroups and variables in formula (Ig) have the same meanings, includingthe same preferred meanings, as described and defined herein above forthe compound of formula (I).

In a further embodiment, the compound of formula (I) is a compound ofthe following formula (Ih) or a pharmaceutically acceptable salt orsolvate thereof:

wherein R¹ and R² in formula (Ih) are joined together to form a moiety(A2) as defined herein above, wherein R³ and R⁴ are each —NH₃, andwherein the further groups and variables in formula (Ih) have the samemeanings, including the same preferred meanings, as described anddefined herein above for the compound of formula (I).

In a further embodiment, the compound of formula (I) is a compound ofthe following formula (i) or a pharmaceutically acceptable salt orsolvate thereof:

wherein R¹ and R² in formula (Ii) are joined together to form a moiety(A3) as defined herein above, and wherein the further groups andvariables in formula (Ii) have the same meanings, including the samepreferred meanings, as described and defined herein above for thecompound of formula (I).

In a further embodiment, the compound of formula (I) is a compound ofthe following formula (Ij) or a pharmaceutically acceptable salt orsolvate thereof:

wherein R³ in formula (Ij) is a moiety (B2) as defined herein above,wherein R⁴ is —NH₃, and wherein the further groups and variables informula (Ij) have the same meanings, including the same preferredmeanings, as described and defined herein above for the compound offormula (I).

For a person skilled in the field of synthetic chemistry, various waysfor the preparation of the compounds of formula (I) will be readilyapparent. For example, the compounds of formula (I) can be prepared asdescribed in the following and, in particular, they can be prepared inaccordance with or in analogy to the synthetic routes described inExample 1.

Preparation of the Platinum(II) Precursors:

The platinum(II) precursors (P2) can be synthesized out of potassiumtetrachloridoplatinate (P1) in aqueous solution, either using thecorresponding amine ligands (E1) according to Kidani, Y; Inagaki, K. J.Med. Chem. 1978, 21(12), 1315-1318 or using ammonia (R³ and R⁴ are each:—NH₃) according to Dhara, S. Ch. Indian J. Chem. 1970, 8(2), 193-194.(P2) precursors, where R³ is a (B2) moiety and R⁴ is —NH₃ can besynthesized out of (P2), where R³ and R⁴ are each —NH₃, according toGiandomenico, C. M. et al. Inorg. Chem. 1995, 34, 1015-1021.

The platinum(II) precursors (P3) can be synthesized out of theprecursors (P2) in aqueous solution using AgNO₃ or Ag₂SO₄ and thecorresponding ligands R¹ and R², wherein R¹ and R² are joined togetherto form a moiety (A1), (A2) or (A3) (Kidani, Y; Inagaki, K. J. Med.Chem. 1978, 21(12), 1315-1318 or Rochon, F. D.; Gruia, L. M. Inorg.Chim. Acta 2000, 306, 193-204).

Preparation of the Platinum(IV) Precursors:

The platinum(IV) precursors (P5) can be synthesized out of theplatinum(II) precursors (P3) using the corresponding ligand R⁷COOH asthe solvent and H₂O₂ according to Lee, Y.-A.; Jung, S. M.; Kang, S. W.;Jung, O.-S. Transition Met. Chem. 2004, 29, 710-713.

Alternatively, other organic solvents, like tetrahydrofuran ordichloromethane, as well as other oxidizing reagents, like tert-butylhydroperoxide, can be used for preparation of (P5) (Zhang, J. Z. et al.Chem. Eur. J. 2013, 19, 1672-1676).

Another synthesis route for preparation of (P5) is a two-step procedurevia the platinum precursors (P4). (P4) can be prepared by oxidation of(P3) with H₂O₂ in aqueous solution. In a second step, R⁷COOH as anisocyanate, symmetric or asymmetric anhydride, or acyl chloride can beattached to (P4) in an organic solvent like DMF or acetone (with orwithout pyridine) (in the scheme below, the use of an isocyanatereactant R—N═C═O results in the formation of a compound (P5), wherein—R⁷ is —NH—R; the group R in the isocyanate reactant can thus beselected to provide a corresponding amino-containing group R⁷ as definedin connection with the compound of formula (I)). Alternatively, anypeptide-coupling reagent like DCC (N,N′dicyclohexylcarbodiimide) or TBTU(N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate)in an organic solvent can be used for coupling of RCOOH to (P4) (Zhang,J. Z. et al. Chem. Eur. J. 2013, 19, 1672-1676).

General Procedure for the Preparation of Isocyanates:

To a solution of the corresponding carboxylic acid in an organic solventlike acetone and 1.0-1.2 eq. of a base like triethylamine (at about −5°C.), an alkyl chloroformate like ethyl chloroformate (1.0-1.2 eq.) in anorganic solvent like acetone is added. Subsequently, NaN₃ (1 eq.) isadded and stirring is continued without cooling for 20-60 min. Thereaction mixture is poured into water and extracted with toluene. Thecombined organic layers are dried over MgSO₄ and heated to reflux at120-140° C. for 50-100 min. After removal of the solvent under reducedpressure, the crude product can be used without further purification.

General Procedure for the Preparation of Anhydrides:

Symmetric anhydrides can be prepared using triphosgene. Asymmetricanhydrides can be synthesized either using acetic anhydride (Höfer, D etal. J. Inorg. Biochem. in press, doi:10.1016/j.jinorgbio.2015.08.018),acyl chlorides (Kim, S. et al. J Org. Chem. 1985, 50, 560-565) oralkylchloroformates.

General Procedure for the Preparation of Acyl Chlorides:

Acyl chlorides can be prepared using for example oxalyl chloride anddimethylformamide as a catalyst (Mantovani, G. et al. J. Am. Chem. Soc.2005, 127, 2966-2973).

Preparation of Compounds of Formula (I):

The compounds of formula (I) can be synthesized out of the platinum(IV)precursors (P5) using the maleimide-containing ligand as isocyanate,symmetric or asymmetric anhydride or acyl chloride in an organic solventlike DMF or acetone (with or without pyridine). Alternatively, anypeptide-coupling reagent like DCC (N,N′dicyclohexylcarbodiimide) or TBTU(N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate)etc. in an organic solvent can be used for coupling of themaleimide-containing ligand to (P5) (Zhang, J. Z. et al. Chem. Eur. J.2013, 19, 1672-1676).

Alternatively, the maleimide-containing ligand as an isocyanate,symmetric or asymmetric anhydride or acyl chloride in an organic solventlike DMF or acetone (with or without pyridine) can be attached toprecursor (P4) first to form (P6). Alternatively, any peptide-couplingreagent like DCC (N,N′-dicyclohexylcarbodiimide) or TBTU(N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate)in an organic solvent can be used for coupling of themaleimide-containing ligand to form (P6) (Zhang, J. Z. et al. Chem. Eur.J. 2013, 19, 1672-1676).

In a second step, R⁰COOH as isocyanate, symmetric or asymmetricanhydride or acyl chloride can be attached to (P6) in an organic solventlike DMF or acetone (with or without pyridine) to form the correspondingcompound of formula (I). Alternatively, any peptide-coupling reagentlike DCC (N,N′-dicyclohexylcarbodiimide) or TBTU(N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate)in an organic solvent can be used for coupling of RCOOH to (P6) to formthe corresponding compound of formula (I) (Zhang, J. Z. et al. Chem.Eur. J. 2013, 19, 1672-1676).

The following definitions apply throughout the present specification,unless specifically indicated otherwise.

As used herein, the term “hydrocarbon group” refers to agroup consistingof carbon atoms and hydrogen atoms.

As used herein, the term “alkyl” refers to a monovalent saturatedacyclic (i.e., non-cyclic) hydrocarbon group which may be linear orbranched. Accordingly, an “alkyl” group does not comprise anycarbon-to-carbon double bond or any carbon-to-carbon triple bond. A“C₁₋₈ alkyl” denotes an alkyl group having 1 to 8 carbon atoms.Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g.,n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, ortert-butyl). Unless defined otherwise, the term “alkyl” preferablyrefers to C₁₋₄ alkyl, more preferably to methyl or ethyl, and even morepreferably to methyl.

As used herein, the term “alkenyl” refers to a monovalent unsaturatedacyclic hydrocarbon group which may be linear or branched and comprisesone or more (e.g., one or two) carbon-to-carbon double bonds while itdoes not comprise any carbon-to-carbon triple bond. The term “C₂₋₈alkenyl” denotes an alkenyl group having 2 to 8 carbon atoms. Preferredexemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1-en-1-yl,prop-1-en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g.,buta-1,3-dien-1-yl or buta-1,3-dien-2-yl), pentenyl, or pentadienyl(e.g., isoprenyl). Unless defined otherwise, the term “alkenyl”preferably refers to C₂₋₄ alkenyl.

As used herein, the term “alkynyl” refers to a monovalent unsaturatedacyclic hydrocarbon group which may be linear or branched and comprisesone or more (e.g., one or two) carbon-to-carbon triple bonds andoptionally one or more carbon-to-carbon double bonds. The term “C₂₋₈alkynyl” denotes an alkynyl group having 2 to 8 carbon atoms. Preferredexemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), orbutynyl. Unless defined otherwise, the term “alkynyl” preferably refersto C₂₋₄ alkynyl.

As used herein, the term “alkylene” refers to an alkanediyl group, i.e.a divalent saturated acyclic hydrocarbon group, which may be linear orbranched. A “C₁₋₈ alkylene” denotes an alkylene group having 1 to 8carbon atoms, and the term “C₀₋₃ alkylene” indicates that a covalentbond (corresponding to the option “C₀ alkylene”) or a C₁₋₃ alkylene ispresent. Preferred exemplary alkylene groups are methylene (—CH₂—),ethylene (e.g., —CH₂—CH₂— or —CH(—CH₃)—), propylene (e.g.,—CH₂—CH₂—CH₂—, —CH(—CH₂—CH₃)—, —CH₂—CH(—CH₃)—, or —CH(—CH₃)—CH₂—), orbutylene (e.g., —CH₂—CH₂—CH₂—CH₂—). Unless defined otherwise, the term“alkylene” preferably refers to C₁₋₄ alkylene (including, in particular,linear C₁₋₄ alkylene), more preferably to methylene or ethylene.

As used herein, the term “aryl” refers to an aromatic hydrocarbon ringgroup, including monocyclic aromatic rings as well as bridged ringand/or fused ring systems containing at least one aromatic ring (e.g.,ring systems composed of two or three fused rings, wherein at least oneof these fused rings is aromatic; or bridged ring systems composed oftwo or three rings, wherein at least one of these bridged rings isaromatic). “Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e.,1,2-dihydronaphthyl), tetralinyl (i.e., 1,2,3,4-tetrahydronaphthyl),indanyl, indenyl (e.g., 1H-indenyl), anthracenyl, phenanthrenyl,9H-fluorenyl, or azulenyl. Unless defined otherwise, an “aryl”preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms,even more preferably refers to phenyl or naphthyl, and most preferablyrefers to phenyl.

As used herein, the term “arylene” refers to an aryl group, as definedherein above, but having two points of attachment, i.e. a divalentaromatic hydrocarbon ring group, including monocyclic aromatic rings aswell as bridged ring and/or fused ring systems containing at least onearomatic ring (e.g., ring systems composed of two or three fused rings,wherein at least one of these fused rings is aromatic; or bridged ringsystems composed of two or three rings, wherein at least one of thesebridged rings is aromatic). “Arylene” may, e.g., refer to phenylene(e.g., phen-1,2-diyl, phen-1,3-diyl, or phen-1,4-diyl), naphthylene(e.g., naphthalen-1,2-diyl, naphthalen-1,3-diyl, naphthalen-1,4-diyl,naphthalen-1,5-diyl, naphthalen-1,6-diyl, naphthalen-1,7-diyl,naphthalen-2,3-diyl, naphthalen-2,5-diyl, naphthalen-2,6-diyl,naphthalen-2,7-diyl, or naphthalen-2,8-diyl), 1,2-dihydronaphthylene,1,2,3,4-tetrahydronaphthylene, indanylene, indenylene, anthracenylene,phenanthrenylene, 9H-fluorenylene, or azulenylene. Unless definedotherwise, an “arylene” preferably has 6 to 14 ring atoms, morepreferably 6 to 10 ring atoms, even more preferably refers to phenyleneor naphthylene, and most preferably refers to phenylene (particularlyphen-1,4-diyl).

As used herein, the term “heteroaryl” refers to an aromatic ring group,including monocyclic aromatic rings as well as bridged ring and/or fusedring systems containing at least one aromatic ring (e.g., ring systemscomposed of two or three fused rings, wherein at least one of thesefused rings is aromatic; or bridged ring systems composed of two orthree rings, wherein at least one of these bridged rings is aromatic),wherein said aromatic ring group comprises one or more (such as, e.g.,one, two, three, or four) ring heteroatoms independently selected fromO, S and N, and the remaining ring atoms are carbon atoms, wherein oneor more S ring atoms (if present) and/or one or more N ring atoms (ifpresent) may optionally be oxidized, and further wherein one or morecarbon ring atoms may optionally be oxidized (i.e., to form an oxogroup). For example, each heteroatom-containing ring comprised in saidaromatic ring group may contain one or two O atoms and/or one or two Satoms (which may optionally be oxidized) and/or one, two, three, or fourN atoms (which may optionally be oxidized), provided that the totalnumber of heteroatoms in the corresponding heteroatom-containing ring is1 to 4 and that there is at least one carbon ring atom (which mayoptionally be oxidized) in the corresponding heteroatom-containing ring.“Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl),benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e.,furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g.,2H-1-benzopyranyl or 4H-1-benzopyranyl), isochromenyl (e.g.,1H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl(e.g., 2H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl;e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl,pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl,indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl(e.g., [1,10]phenanthrolinyl, [1,7]phenanthrolinyl, or[4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl,phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g.,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (i.e., furazanyl), or1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, or 1,3,4-thiadiazolyl), phenoxazinyl,pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl),1,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl,benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl),triazolyl (e.g., 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl,1H-1,2,4-triazolyl, or 4H-1,2,4-triazolyl), benzotriazolyl,1H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl,1,2,4-triazinyl, or 1,3,5-triazinyl), furo[2,3-c]pyridinyl,dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or1,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g.,imidazo[1,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl,thienopyridinyl, tetrahydrothienopyridinyl (e.g.,4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl,1,3-benzodioxolyl, benzodioxanyl (e.g., 1,3-benzodioxanyl or1,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term“heteroaryl” preferably refers to a 5- to 14-membered (more preferably5- to 10-membered) monocyclic ring or fused ring system comprising oneor more (e.g., one, two, three or four) ring heteroatoms independentlyselected from O, S and N, wherein one or more S ring atoms (if present)and/or one or more N ring atoms (if present) are optionally oxidized,and wherein one or more carbon ring atoms are optionally oxidized; evenmore preferably, a “heteroaryl” refers to a 5- or 6-membered monocyclicring comprising one or more (e.g., one, two or three) ring heteroatomsindependently selected from O, S, and N, wherein one or more S ringatoms (if present) and/or one or more N ring atoms (if present) areoptionally oxidized, and wherein one or more carbon ring atoms areoptionally oxidized. Moreover, unless defined otherwise, the term“heteroaryl” particularly preferably refers to pyridinyl (e.g.,2-pyridyl, 3-pyridyl, or 4-pyridyl), imidazolyl, thiazolyl,1H-tetrazolyl, 2H-tetrazolyl, thienyl (i.e., thiophenyl), orpyrimidinyl.

As used herein, the term “heteroarylene” refers to a heteroaryl group,as defined herein above, but having two points of attachment, i.e. adivalent aromatic ring group, including monocyclic aromatic rings aswell as bridged ring and/or fused ring systems containing at least onearomatic ring (e.g., ring systems composed of two or three fused rings,wherein at least one of these fused rings is aromatic; or bridged ringsystems composed of two or three rings, wherein at least one of thesebridged rings is aromatic), wherein said aromatic ring group comprisesone or more (such as, e.g., one, two, three, or four) ring heteroatomsindependently selected from O, S and N, and the remaining ring atoms arecarbon atoms, wherein one or more S ring atoms (if present) and/or oneor more N ring atoms (if present) may optionally be oxidized, andfurther wherein one or more carbon ring atoms may optionally be oxidized(i.e., to form an oxo group). For example, each heteroatom-containingring comprised in said aromatic ring group may contain one or two Oatoms and/or one or two S atoms (which may optionally be oxidized)and/or one, two, three, or four N atoms (which may optionally beoxidized), provided that the total number of heteroatoms in thecorresponding heteroatom-containing ring is 1 to 4 and that there is atleast one carbon ring atom (which may optionally be oxidized) in thecorresponding heteroatom-containing ring. “Heteroarylene” may, e.g.,refer to thienylene (i.e., thiophenylene; e.g., thien-2,3-diyl,thien-2,4-diyl, or thien-2,5-diyl), benzo[b]thienylene,naphtho[2,3-b]thienylene, thianthrenylene, furylene (i.e., furanylene;e.g., furan-2,3-diyl, furan-2,4-diyl, or furan-2,5-diyl),benzofuranylene, isobenzofuranylene, chromanylene, chromenylene,isochromenylene, chromonylene, xanthenylene, phenoxathiinylene,pyrrolylene, imidazolylene, pyrazolylene, pyridylene (i.e.,pyridinylene), pyrazinylene, pyrimidinylene, pyridazinylene, indolylene,isoindolylene, indazolylene, indolizinylene, purinylene, quinolylene,isoquinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene,cinnolinylene, pteridinylene, carbazolylene, β-carbolinylene,phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene,phenazinylene, thiazolylene (e.g., thiazol-2,4-diyl, thiazol-2,5-diyl,or thiazol-4,5-diyl), isothiazolylene (e.g., isothiazol-3,4-diyl,isothiazol-3,5-diyl, or isothiazol-4,5-diyl), phenothiazinylene,oxazolylene (e.g., oxazol-2,4-diyl, oxazol-2,5-diyl, oroxazol-4,5-diyl), isoxazolylene (e.g., isoxazol-3,4-diyl,isoxazol-3,5-diyl, or isoxazol-4,5-diyl), oxadiazolylene (e.g.,1,2,4-oxadiazol-3,5-diyl, 1,2,5-oxadiazol-3,4-diyl, or1,3,4-oxadiazol-2,5-diyl), thiadiazolylene (e.g.,1,2,4-thiadiazol-3,5-diyl, 1,2,5-thiadiazol-3,4-diyl, or1,3,4-thiadiazol-2,5-diyl), phenoxazinylene,pyrazolo[1,5-a]pyrimidinylene, 1,2-benzoisoxazolylene,benzothiazolylene, benzothiadiazolylene, benzoxazolylene,benzisoxazolylene, benzimidazolylene, benzo[b]thiophenylene (i.e.,benzothienylene), triazolylene (e.g., 1H-1,2,3-triazolylene,2H-1,2,3-triazolylene, 1H-1,2,4-triazolylene, or 4H-1,2,4-triazolylene),benzotriazolylene, 1H-tetrazolylene, 2H-tetrazolylene, triazinylene(e.g., 1,2,3-triazinylene, 1,2,4-triazinylene, or 1,3,5-triazinylene),furo[2,3-c]pyridinylene, dihydrofuropyridinylene (e.g.,2,3-dihydrofuro[2,3-c]pyridinylene or1,3-dihydrofuro[3,4-c]pyridinylene), imidazopyridinylene (e.g.,imidazo[1,2-a]pyridinylene or imidazo[3,2-a]pyridinylene),quinazolinylene, thienopyridinylene, tetrahydrothienopyridinylene (e.g.,4,5,6,7-tetrahydrothieno[3,2-c]pyridinylene), dibenzofuranylene,1,3-benzodioxolylene, benzodioxanylene (e.g., 1,3-benzodioxanylene or1,4-benzodioxanylene), or coumarinylene. Unless defined otherwise, theterm “heteroarylene” preferably refers to a divalent 5- to 14-membered(more preferably 5- to 10-membered) monocyclic ring or fused ring systemcomprising one or more (e.g., one, two, three or four) ring heteroatomsindependently selected from O, S and N, wherein one or more S ring atoms(if present) and/or one or more N ring atoms (if present) are optionallyoxidized, and wherein one or more carbon ring atoms are optionallyoxidized; even more preferably, a “heteroarylene” refers to a divalent5- or 6-membered monocyclic ring comprising one or more (e.g., one, twoor three) ring heteroatoms independently selected from O, S, and N,wherein one or more S ring atoms (if present) and/or one or more N ringatoms (if present) are optionally oxidized, and wherein one or morecarbon ring atoms are optionally oxidized. A “heteroarylene”, includingany of the specific heteroarylene groups described herein, may beattached through two carbon ring atoms, particularly through those twocarbon ring atoms that have the greatest distance from one another (interms of the number of ring atoms separating them by the shortestpossible connection) within one single ring or within the entire ringsystem of the corresponding heteroarylene. Moreover, unless definedotherwise, the term “heteroarylene” particularly preferably refers topyridinylene, imidazolylene, thiazolylene, 1H-tetrazolylene,2H-tetrazolylene, thienylene (i.e., thiophenylene), or pyrimidinylene.

As used herein, the term “cycloalkyl” refers to a saturated hydrocarbonring group, including monocyclic rings as well as bridged ring, spiroring and/or fused ring systems (which may be composed, e.g., of two orthree rings; such as, e.g., a fused ring system composed of two or threefused rings). “Cycloalkyl” may, e.g., refer to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e.,decahydronaphthyl), or adamantyl. Unless defined otherwise, “cycloalkyl”preferably refers to a C₃₋₁₁ cycloalkyl, and more preferably refers to aC₃₋₇ cycloalkyl. A particularly preferred “cycloalkyl” is a monocyclicsaturated hydrocarbon ring having 3 to 7 ring members. Moreover, unlessdefined otherwise, the term “cycloalkyl” even more preferably refers tocyclohexyl or cyclopropyl, and yet even more preferably refers tocyclohexyl.

As used herein, the term “heterocycloalkyl” refers to a saturated ringgroup, including monocyclic rings as well as bridged ring, spiro ringand/or fused ring systems (which may be composed, e.g., of two or threerings; such as, e.g., a fused ring system composed of two or three fusedrings), wherein said ring group contains one or more (such as, e.g.,one, two, three, or four) ring heteroatoms independently selected fromO, S and N, and the remaining ring atoms are carbon atoms, wherein oneor more S ring atoms (if present) and/or one or more N ring atoms (ifpresent) may optionally be oxidized, and further wherein one or morecarbon ring atoms may optionally be oxidized (i.e., to form an oxogroup). For example, each heteroatom-containing ring comprised in saidsaturated ring group may contain one or two O atoms and/or one or two Satoms (which may optionally be oxidized) and/or one, two, three or fourN atoms (which may optionally be oxidized), provided that the totalnumber of heteroatoms in the corresponding heteroatom-containing ring is1 to 4 and that there is at least one carbon ring atom (which mayoptionally be oxidized) in the corresponding heteroatom-containing ring.“Heterocycloalkyl” may, e.g., refer to aziridinyl, azetidinyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl,azepanyl, diazepanyl (e.g., 1,4-diazepanyl), oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g.,morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl,oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl,tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, thiiranyl, thietanyl,tetrahydrothiophenyl (i.e., thiolanyl), 1,3-dithiolanyl, thianyl,thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless defined otherwise,“heterocycloalkyl” preferably refers to a 3- to 11-membered saturatedring group, which is a monocyclic ring or a fused ring system (e.g., afused ring system composed of two fused rings), wherein said ring groupcontains one or more (e.g., one, two, three, or four) ring heteroatomsindependently selected from O, S and N, wherein one or more S ring atoms(if present) and/or one or more N ring atoms (if present) are optionallyoxidized, and wherein one or more carbon ring atoms are optionallyoxidized; more preferably, “heterocycloalkyl” refers to a 5- to7-membered saturated monocyclic ring group containing one or more (e.g.,one, two, or three) ring heteroatoms independently selected from O, Sand N, wherein one or more S ring atoms (if present) and/or one or moreN ring atoms (if present) are optionally oxidized, and wherein one ormore carbon ring atoms are optionally oxidized. Moreover, unless definedotherwise, “heterocycloalkyl” even more preferably refers totetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl,or tetrahydrofuranyl.

As used herein, the term “halogen” refers to fluoro (—F), chloro (—Cl),bromo (—Br), or iodo (—I).

As used herein, the term “haloalkyl” refers to an alkyl groupsubstituted with one or more (preferably 1 to 6, more preferably 1 to 3)halogen atoms which are selected independently from fluoro, chloro,bromo and iodo, and are preferably all fluoro atoms. It will beunderstood that the maximum number of halogen atoms is limited by thenumber of available attachment sites and, thus, depends on the number ofcarbon atoms comprised in the alkyl moiety of the haloalkyl group.“Haloalkyl” may, e.g., refer to —CF₃, —CHF₂, —CH₂F, —CF₂—CH₃, —CH₂—CF₃,—CH₂—CHF₂, —CH₂—CF₂—CH₃, —CH₂—CF₂—CF₃, or —CH(CF₃)₂. A particularlypreferred “haloalkyl” group is —CF₃.

As used herein, the terms “optional”, “optionally” and “may” denote thatthe indicated feature may be present but can also be absent. Wheneverthe term “optional”, “optionally” or “may” is used, the presentinvention specifically relates to both possibilities, i.e., that thecorresponding feature is present or, alternatively, that thecorresponding feature is absent. For example, the expression “X isoptionally substituted with Y” (or “X may be substituted with Y”) meansthat X is either substituted with Y or is unsubstituted. Likewise, if acomponent of a composition is indicated to be “optional”, the inventionspecifically relates to both possibilities, i.e., that the correspondingcomponent is present (contained in the composition) or that thecorresponding component is absent from the composition.

Various groups are referred to as being “optionally substituted” in thisspecification. Generally, these groups may carry one or moresubstituents, such as, e.g., one, two, three or four substituents. Itwill be understood that the maximum number of substituents is limited bythe number of attachment sites available on the substituted moiety.Unless defined otherwise, the “optionally substituted” groups referredto in this specification carry preferably not more than two substituentsand may, in particular, carry only one substituent. Moreover, unlessdefined otherwise, it is preferred that the optional substituents areabsent, i.e. that the corresponding groups are unsubstituted.

As used herein, unless explicitly indicated otherwise or contradicted bycontext, the terms “a”, “an” and “the” are used interchangeably with“one or more” and “at least one”. Thus, for example, a compositioncomprising “a” compound of formula (I) can be interpreted as referringto a composition comprising “one or more” compounds of formula (I).

As used herein, the term “about” preferably refers to ±10% of theindicated numerical value, more preferably to ±5% of the indicatednumerical value, and in particular to the exact numerical valueindicated.

As used herein, the term “comprising” (or “comprise”, “comprises”,“contain”, “contains”, or “containing”), unless explicitly indicatedotherwise or contradicted by context, has the meaning of “containing,interalia”, i.e., “containing, among further optional elements, . . . ”.In addition thereto, this term also includes the narrower meanings of“consisting essentially of” and “consisting of”. For example, the term“A comprising B and C” has the meaning of “A containing, inter alia, Band C”, wherein A may contain further optional elements (e.g., “Acontaining B, C and D” would also be encompassed), but this term alsoincludes the meaning of “A consisting essentially of B and C” and themeaning of “A consisting of B and C” (i.e., no other components than Band C are comprised in A).

The scope of the invention embraces all pharmaceutically acceptable saltforms of the compounds of formula (I) which may be formed, e.g., byprotonation of an atom carrying an electron lone pair, which issusceptible to protonation, such as an amino group, with an inorganic ororganic acid, or as a salt of an acid group (such as a carboxylic acidgroup) with a physiologically acceptable cation. Exemplary base additionsalts comprise, for example: alkali metal salts such as sodium orpotassium salts; alkaline earth metal salts such as calcium or magnesiumsalts; zinc salts; ammonium salts; aliphatic amine salts such astrimethylamine, triethylamine, dicyclohexylamine, ethanolamine,diethanolamine, triethanolamine, procaine salts, meglumine salts,ethylenediamine salts, or choline salts; aralkyl amine salts such asN,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts;heterocyclic aromatic amine salts such as pyridine salts, picolinesalts, quinoline salts or isoquinoline salts; quaternary ammonium saltssuch as tetramethylammonium salts, tetraethylammonium salts,benzyltrimethylammonium salts, benzyltriethylammonium salts,benzyltributylammonium salts, methyltrioctylammonium salts ortetrabutylammonium salts; and basic amino acid salts such as argininesalts, lysine salts, or histidine salts. Exemplary acid addition saltscomprise, for example: mineral acid salts such as hydrochloride,hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate orhydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g.,phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonatesalts, hydrogencarbonate salts, perchlorate salts, borate salts, orthiocyanate salts; organic acid salts such as acetate, propionate,butyrate, pentanoate, hexanoate, heptanoate, octanoate,cyclopentanepropionate, decanoate, undecanoate, oleate, stearate,lactate, maleate, oxalate, fumarate, tartrate, malate, citrate,succinate, adipate, gluconate, glycolate, nicotinate, benzoate,salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate,or pivalate salts; sulfonate salts such as methanesulfonate (mesylate),ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate),benzenesulfonate (besylate), p-toluenesulfonate (tosylate),2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, orcamphorsulfonate salts; glycerophosphate salts; and acidic amino acidsalts such as aspartate or glutamate salts. If the compound of formula(I) is in the form of a pharmaceutically acceptable salt, it ispreferably in the form of a hydrochloride salt. Most preferably,however, the compound of formula (I), including any one of the specificcompounds of formula (I) described herein (such as KP2299), is not inthe form of a salt.

Moreover, the scope of the invention embraces the compounds of formula(I) in any solvated form, including, e.g., solvates with water (i.e., asa hydrate) or solvates with organic solvents such as, e.g., methanol,ethanol or acetonitrile (i.e., as a methanolate, ethanolate oracetonitrilate), or in any crystalline form (i.e., as any polymorph), orin amorphous form. It is to be understood that such solvates of thecompounds of the formula (I) also include solvates of pharmaceuticallyacceptable salts of the compounds of the formula (I).

Furthermore, the compounds of formula (I) may exist in the form ofdifferent isomers, in particular stereoisomers (including, e.g.,geometric isomers (or cis/trans isomers), enantiomers and diastereomers)or tautomers. All such isomers of the compounds of formula (I) arecontemplated as being part of the present invention, either in admixtureor in pure or substantially pure form. As for stereoisomers, theinvention embraces the isolated optical isomers of the compoundsaccording to the invention as well as any mixtures thereof (including,in particular, racemic mixtures/racemates). The racemates can beresolved by physical methods, such as, e.g., fractional crystallization,separation or crystallization of diastereomeric derivatives, orseparation by chiral column chromatography. The individual opticalisomers can also be obtained from the racemates via salt formation withan optically active acid followed by crystallization. In particular, ifone or both of the ligand pairs R¹/R² and R³/R⁴ is/are asymmetric, e.g.,due to their substitution pattern or the presence of moiety (A3) and/ormoiety (B2), the platinum(IV) atom in the corresponding compound offormula (I) will form a stereocenter, resulting in stereoisomers thatdiffer with respect to the orientation of the two axial ligands (i.e.,the axial ligand containing R⁵ and R⁶, and the axial ligand containingR⁷), such as, e.g., the stereoisomers 18 and 19 as depicted hereinabove; any such stereoisomers of the compounds of formula (I) arelikewise encompassed by the present invention. The present inventionfurther encompasses any tautomers of the compounds provided herein.

The scope of the invention also embraces compounds of formula (I), inwhich one or more atoms are replaced by a specific isotope of thecorresponding atom. For example, the invention encompasses compounds offormula (I), in which one or more hydrogen atoms (or, e.g., all hydrogenatoms) are replaced by deuterium atoms (i.e., ²H; also referred to as“D”). Accordingly, the invention also embraces compounds of formula (I)which are enriched in deuterium. Naturally occurring hydrogen is anisotopic mixture comprising about 99.98 mol-% hydrogen-1 (¹H) and about0.0156 mol-% deuterium (²H or D). The content of deuterium in one ormore hydrogen positions in the compounds of formula (I) can be increasedusing deuteration techniques known in the art. For example, a compoundof formula (I) or a reactant or precursor to be used in the synthesis ofthe compound of formula (I) can be subjected to an H/D exchange reactionusing, e.g., heavy water (D20). Further suitable deuteration techniquesare described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667,2012; William J S et al., Journal of Labelled Compounds andRadiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J OrgChem, 79, 5861-5868, 2014. The content of deuterium can be determined,e.g., using mass spectrometry or NMR spectroscopy. Unless specificallyindicated otherwise, it is preferred that the compound of formula (I) isnot enriched in deuterium. Accordingly, the presence of naturallyoccurring hydrogen atoms or ¹H hydrogen atoms in the compounds offormula (I) is preferred.

The present invention also embraces compounds of formula (I), in whichone or more atoms are replaced by a positron-emitting isotope of thecorresponding atom, such as, e.g., ¹⁸F, ¹¹C, ¹³N, ¹⁵O, ⁷⁶Br, ⁷⁷Br, ¹²⁰Iand/or ¹²⁴I. Such compounds can be used as tracers or imaging probes inpositron emission tomography (PET). The invention thus includes (i)compounds of formula (I), in which one or more fluorine atoms (or, e.g.,all fluorine atoms) are replaced by ¹⁸F atoms, (ii) compounds of formula(I), in which one or more carbon atoms (or, e.g., all carbon atoms) arereplaced by ¹¹C atoms, (iii) compounds of formula (I), in which one ormore nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by ¹³Natoms, (iv) compounds of formula (I), in which one or more oxygen atoms(or, e.g., all oxygen atoms) are replaced by 150 atoms, (v) compounds offormula (I), in which one or more bromine atoms (or, e.g., all bromineatoms) are replaced by ⁷⁶Br atoms, (vi) compounds of formula (I), inwhich one or more bromine atoms (or, e.g., all bromine atoms) arereplaced by ⁷⁷Br atoms, (vii) compounds of formula (I), in which one ormore iodine atoms (or, e.g., all iodine atoms) are replaced by ¹²⁰Iatoms, and (viii) compounds of formula (I), in which one or more iodineatoms (or, e.g., all iodine atoms) are replaced by ¹²⁴I atoms. Ingeneral, it is preferred that none of the atoms in the compounds offormula (I) are replaced by specific isotopes.

The compounds provided herein may be administered as compounds per se ormay be formulated as medicaments. The medicaments/pharmaceuticalcompositions may optionally comprise one or more pharmaceuticallyacceptable excipients, such as carriers, diluents, fillers,disintegrants, lubricating agents, binders, colorants, pigments,stabilizers, preservatives, antioxidants, and/or solubility enhancers.

The pharmaceutical compositions may comprise one or more solubilityenhancers, such as, e.g., poly(ethylene glycol), including poly(ethyleneglycol) having a molecular weight in the range of about 200 to about5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol,propylene glycol, glycerol, a non-ionic surfactant, tyloxapol,polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine,dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, acyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin,hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin,hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin,dihydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin,sulfobutylether-γ-cyclodextrin, glucosyl-α-cyclodextrin,glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin,maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin,maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin,maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin,methyl-β-cyclodextrin, a carboxyalkyl thioether, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a vinylacetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctylsodium sulfosuccinate, or any combination thereof.

The pharmaceutical compositions can be formulated by techniques known tothe person skilled in the art, such as the techniques published in“Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press,22^(nd) edition. The pharmaceutical compositions can be formulated asdosage forms for oral, parenteral, such as intramuscular, intravenous,subcutaneous, intradermal, intraarterial, or intraperitoneal (especiallyin form of hyperthermic chemoperfusion) administration. Dosage forms fororal administration include coated and uncoated tablets, soft gelatincapsules, hard gelatin capsules, lozenges, troches, solutions,emulsions, suspensions, syrups, elixirs, powders and granules forreconstitution, dispersible powders and granules, medicated gums,chewing tablets and effervescent tablets. Dosage forms for parenteraladministration include solutions, emulsions, suspensions, dispersionsand powders, and granules for reconstitution. Emulsions are a preferreddosage form for parenteral administration.

The compounds of formula (I) or the above described pharmaceuticalcompositions comprising a compound of formula (I) may be administered toa subject by any convenient route of administration, whethersystemically/peripherally or at the site of desired action, includingbut not limited to one or more of: oral (e.g., as a tablet, capsule, oras an ingestible solution), parenteral (e.g., using injection techniquesor infusion techniques, and including, for example, by injection, e.g.,subcutaneous, intradermal, intramuscular, intravenous, intraarterial,intracardiac, intrathecal, intraspinal, intracapsular, subcapsular,intraorbital, intraperitoneal, intratracheal, subcuticular,intraarticular, subarachnoid, or intrasternal by, e.g., implant of adepot, for example, subcutaneously or intramuscularly), pulmonary (e.g.,by inhalation or insufflation therapy using, e.g., an aerosol, e.g.,through mouth or nose), gastrointestinal, intrauterine, intraocular,subcutaneous, or ophthalmic (including intravitreal or intracameral)administration.

If said compounds or pharmaceutical compositions are administeredparenterally, then examples of such administration include one or moreof: intravenously, intraarterially, intraperitoneally, intrathecally,intraventricularly, intraurethrally, intrasternally, intracardially,intracranially, intramuscularly or subcutaneously administering thecompounds or pharmaceutical compositions, and/or by using infusiontechniques. For parenteral administration, the compounds are best usedin the form of a sterile aqueous solution, which may contain othersubstances, for example, enough salts or glucose to make the solutionisotonic with blood. The aqueous solutions should be suitably buffered(preferably to a pH of from 3 to 9), if necessary. The preparation ofsuitable parenteral formulations under sterile conditions is readilyaccomplished by standard pharmaceutical techniques well known to thoseskilled in the art.

Said compounds or pharmaceutical compositions can also be administeredorally in the form of tablets, capsules, ovules, elixirs, solutions orsuspensions, which may contain flavoring or coloring agents, forimmediate-, delayed-, modified-, sustained-, pulsed- orcontrolled-release applications.

The tablets may contain excipients such as microcrystalline cellulose,lactose, sodium citrate, calcium carbonate, dibasic calcium phosphateand glycine, disintegrants such as starch (preferably corn, potato ortapioca starch), sodium starch glycolate, croscarmellose sodium andcertain complex silicates, and granulation binders such aspolyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, stearic acid, glycerylbehenate and talc may be included. Solid compositions of a similar typemay also be employed as fillers in gelatin capsules. Preferredexcipients in this regard include lactose, starch, a cellulose, or highmolecular weight polyethylene glycols. For aqueous suspensions and/orelixirs, the agent may be combined with various sweetening or flavoringagents, coloring matter or dyes, with emulsifying and/or suspendingagents and with diluents such as water, ethanol, propylene glycol andglycerin, and combinations thereof.

Said compounds or pharmaceutical compositions may also be administeredby sustained release systems. Suitable examples of sustained-releasecompositions include semi-permeable polymer matrices in the form ofshaped articles, e.g., films, or microcapsules. Sustained-releasematrices include, e.g., polylactides (see, e.g., U.S. Pat. No.3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate(Sidman, U. et al., Biopolymers 22:547-556 (1983)), poly(2-hydroxyethylmethacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15:167-277(1981), and R. Langer, Chem. Tech. 12:98-105 (1982)), ethylene vinylacetate (R. Langer et al., Id.) or poly-D-(−)-3-hydroxybutyric acid(EP133988). Sustained-release pharmaceutical compositions also includeliposomally entrapped compounds. Liposomes containing a compound of thepresent invention can be prepared by methods known in the art, such as,e.g., the methods described in any one of: DE3218121; Epstein et al.,Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc.Natl. Acad. Sci. (USA) 77:4030-4034 (1980); EP0052322; EP0036676;EP088046; EP0143949; EP0142641; JP 83-118008; U.S. Pat. Nos. 4,485,045;4,544,545; and EP0102324.

Said compounds or pharmaceutical compositions may also be administeredby the pulmonary route or the ocular route. For ophthalmic use, they canbe formulated as micronized suspensions in isotonic, pH adjusted,sterile saline, or, preferably, as solutions in isotonic, pH adjusted,sterile saline, optionally in combination with a preservative such as abenzalkonium chloride. Alternatively, they may be formulated in anointment such as petrolatum.

It is also envisaged to prepare dry powder formulations of the compoundsof formula (I) for pulmonary administration, particularly inhalation.Such dry powders may be prepared by spray drying under conditions, whichresult in a substantially amorphous glassy or a substantiallycrystalline bioactive powder. Accordingly, dry powders of the compoundsof the present invention can be made according to theemulsification/spray drying process disclosed in WO 99/16419 or WO01/85136. Spray drying of solution formulations of the compounds of theinvention can be carried out, e.g., as described generally in the “SprayDrying Handbook”, 5th ed., K. Masters, John Wiley & Sons, Inc., NY(1991), in WO 97/41833, or in WO 03/053411.

The present invention thus relates to the compounds or thepharmaceutical compositions provided herein, wherein the correspondingcompound or pharmaceutical composition is to be administered by any oneof: an oral route; parenteral route using injection techniques orinfusion techniques, including by subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal,intraventricular, intraurethral, or intracranial route; pulmonary route,including by inhalation or insufflation therapy; gastrointestinal route;intrauterine route; intraocular route; subcutaneous route; or ophthalmicroute, including by intravitreal, or intracameral route. Particularlypreferred routes of administration are parenteral administrations like,e.g., intravenous and intraperitoneal (during hyperthermicchemoperfusion).

Typically, a physician will determine the actual dosage, which will bemost suitable for an individual subject. The specific dose level andfrequency of dosage for any particular individual subject may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the individual subjectundergoing therapy.

A proposed, yet non-limiting dose of the compounds according to theinvention for intravenous administration to a human (of approximately 70kg body weight) may be 10 to 1000 mg, preferably 250 to 350 mg, of theactive ingredient (such as KP2299) per unit dose. The unit dose may beadministered, e.g., once every two weeks. It will be appreciated that itmay be necessary to make routine variations to the dosage depending onthe age and weight of the patient/subject as well as the severity of thecondition to be treated. The precise dose and also the route ofadministration will ultimately be at the discretion of the attendantphysician or veterinarian.

The compound of formula (I) or a pharmaceutical composition comprisingthe compound of formula (I) can be administered in monotherapy (e.g.,without concomitant administration of any further therapeutic agents or,in particular, without concomitant administration of any furtheranticancer drugs). However, the compound of formula (I) or apharmaceutical composition comprising the compound of formula (I) canalso be administered in combination with one or more further therapeuticagents. If the compound of formula (I) is used in combination with asecond therapeutic agent active against the same disease or condition(e.g., a further anticancer drug), the dose of each compound may differfrom that when the corresponding compound is used alone, in particular,a lower dose of each compound may be used. The combination of thecompound of formula (I) with one or more further therapeutic agents maycomprise the simultaneous/concomitant administration of the compound offormula (I) and the further therapeutic agent(s) (either in a singlepharmaceutical formulation or in separate pharmaceutical formulations),or the sequential/separate administration of the compound of formula (I)and the further therapeutic agent(s). If administration is sequential,either the compound of formula (I) according to the invention or the oneor more further therapeutic agents may be administered first. Ifadministration is simultaneous, the one or more further therapeuticagents may be included in the same pharmaceutical formulation as thecompound of formula (I), or they may be administered in one or moredifferent (separate) pharmaceutical formulations.

Preferably, the one or more further therapeutic agents to beadministered in combination with a compound of the present invention areanticancer drugs. The anticancer drug(s) to be administered incombination with a compound of formula (I) according to the inventionmay, e.g., be selected from: an angiogenesis inhibitor (e.g., a proteaseinhibitor, a fibroblast growth factor receptor kinase inhibitor, or avascular endothelial growth factor receptor kinase inhibitor); acytostatic drug (e.g., an antimetabolite, such as purine and pyrimidineanalog antimetabolites); an antimitotic agent (e.g., amicrotubule-stabilizing drug or an antimitotic alkaloid); a platinumcoordination complex; an anti-tumor antibiotic; an alkylating agent(e.g., a nitrogen mustard or a nitrosourea); an endocrine agent (e.g.,an adrenocorticosteroid, an androgen, an anti-androgen, an estrogen, ananti-estrogen, an aromatase inhibitor, a gonadotropin-releasing hormoneagonist, or a somatostatin analog); or a compound that targets an enzymeor receptor that is overexpressed and/or otherwise involved in aspecific metabolic pathway that is misregulated/deregulated in the tumorcell (e.g., ATP and GTP phosphodiesterase inhibitors, histonedeacetylase inhibitors, protein kinase inhibitors (such as serine,threonine and tyrosine kinase inhibitors, e.g., Abelson protein tyrosinekinase inhibitors) and the various growth factors, their receptors andcorresponding kinase inhibitors (such as epidermal growth factorreceptor kinase inhibitors, vascular endothelial growth factor receptorkinase inhibitors, fibroblast growth factor inhibitors, insulin-likegrowth factor receptor inhibitors, PI3K inhibitors and platelet-derivedgrowth factor receptor kinase inhibitors)); methionine, aminopeptidaseinhibitors, proteasome inhibitors, cyclooxygenase inhibitors (e.g.,cyclooxygenase-1 or cyclooxygenase-2 inhibitors), topoisomeraseinhibitors (e.g., topoisomerase I inhibitors or topoisomerase IIinhibitors), poly ADP ribose polymerase inhibitors (PARP inhibitors),and epidermal growth factor receptor (EGFR) inhibitors/antagonists. Inaddition, this also includes combination with an immunooncologytherapeutic agent e.g. targeting CTLA-4, PD-1/PD-L1 but also otherimmune-stimulatory strategies.

An alkylating agent which can be used as an anticancer drug incombination with a compound of the present invention may be, forexample, a nitrogen mustard (such as cyclophosphamide, mechlorethamine(chlormethine), uramustine, melphalan, chlorambucil, ifosfamide,bendamustine, or trofosfamide), a nitrosourea (such as carmustine,streptozocin, fotemustine, lomustine, nimustine, prednimustine,ranimustine, or semustine), an alkyl sulfonate (such as busulfan,mannosulfan, or treosulfan), an aziridine (such as hexamethylmelamine(altretamine), triethylenemelamine, ThioTEPA(N,N′N′-triethylenethiophosphoramide), carboquone, or triaziquone), ahydrazine (such as procarbazine), a triazene (such as dacarbazine), oran imidazotetrazine (such as temozolomide).

A platinum coordination complex, which can be used as an anticancer drugin combination with a compound of the present invention may be, forexample, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin,or triplatin tetranitrate.

A cytotoxic drug, which can be used as an anticancer drug in combinationwith a compound of the present invention may be, for example, anantimetabolite, including folic acid analogue antimetabolites (such asaminopterin, methotrexate, pemetrexed, or raltitrexed), purine analogueantimetabolites (such as cladribine, clofarabine, fludarabine,6-mercaptopurine (including its prodrug form azathioprine), pentostatin,or 6-thioguanine), and pyrimidine analogue antimetabolites (such ascytarabine, decitabine, 5-fluorouracil (including its prodrug formscapecitabine and tegafur), floxuridine, gemcitabine, enocitabine, orsapacitabine).

An antimitotic agent, which can be used as an anticancer drug incombination with a compound of the present invention may be, forexample, a taxane (such as docetaxel, larotaxel, ortataxel,paclitaxel/taxol, tesetaxel, or nab-paclitaxel (e.g., Abraxane®)), aVinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine,or vinorelbine), an epothilone (such as epothilone A, epothilone B,epothilone C, epothilone D, epothilone E, or epothilone F) or anepothilone B analogue (such as ixabepilone/azaepothilone B).

An anti-tumor antibiotic, which can be used as an anticancer drug incombination with a compound of the present invention may be, forexample, an anthracycline (such as aclarubicin, daunorubicin,doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin,or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone)or an anti-tumor antibiotic isolated from Streptomyces (such asactinomycin (including actinomycin D), bleomycin, mitomycin (includingmitomycin C), or plicamycin).

A tyrosine kinase inhibitor, which can be used as an anticancer drug incombination with a compound of the present invention may be, forexample, axitinib, bosutinib, cediranib, dasatinib, erlotinib,gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib,sorafenib, sunitinib, axitinib, nintedanib, ponatinib, or vandetanib.

A topoisomerase inhibitor, which can be used as an anticancer drug incombination with a compound of the present invention may be, forexample, a topoisomerase I inhibitor (such as irinotecan, topotecan,camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomeraseII inhibitor (such as amsacrine, etoposide, etoposide phosphate,teniposide, or doxorubicin).

A PARP inhibitor, which can be used as an anticancer drug in combinationwith a compound of the present invention may be, for example, BMN-673,olaparib, rucaparib, veliparib, CEP 9722, MK 4827, BGB-290, or3-aminobenzamide.

An EGFR inhibitor/antagonist, which can be used as an anticancer drug incombination with a compound of the present invention may be, forexample, gefitinib, erlotinib, lapatinib, afatinib, osimertinib,neratinib, ABT-414, dacomitinib, AV-412, PD 153035, vandetanib, PKI-166,pelitinib, canertinib, icotinib, poziotinib, BMS-690514, CUDC-101,AP26113, XL647, cetuximab, panitumumab, zalutumumab, nimotuzumab, ormatuzumab.

Further anticancer drugs may also be used in combination with a compoundof the present invention. The anticancer drugs may comprise biologicalor chemical molecules, like TNF-related apoptosis-inducing ligand(TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, irofulven,trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab,bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib,aminolevulinic acid, methyl aminolevulinate, efaproxiral, porfimersodium, talaporfin, temoporfin, verteporfin, alitretinoin, tretinoin,anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur,celecoxib, demecolcine, elesclomol, elsamitrucin, etoglucid, lonidamine,lucanthone, masoprocol, mitobronitol, mitoguazone, mitotane, oblimersen,omacetaxine, sitimagene, ceradenovec, tegafur, testolactone,tiazofurine, tipifarnib, vorinostat, or iniparib.

Also biological drugs, like antibodies, antibody fragments, antibodyconstructs (for example, single-chain constructs), and/or modifiedantibodies (like CDR-grafted antibodies, humanized antibodies, “fullhumanized” antibodies, etc.) directed against cancer or tumormarkers/factors/cytokines involved in proliferative diseases can beemployed in co-therapy approaches with the compounds of the invention.Examples of such biological molecules are anti-HER2 antibodies (e.g.trastuzumab, Herceptin®), anti-CD20 antibodies (e.g. Rituximab,Rituxan®, MabThera®, Reditux®), anti-CD19/CD3 constructs (see, e.g.,EP1071752) and anti-TNF antibodies (see, e.g., Taylor P C. Antibodytherapy for rheumatoid arthritis. Curr Opin Pharmacol. 2003.3(3):323-328). Further antibodies, antibody fragments, antibodyconstructs and/or modified antibodies to be used in co-therapyapproaches with the compounds of the invention can be found, e.g., in:Taylor P C. Curr Opin Pharmacol. 2003. 3(3):323-328; or Roxana A.Maedica. 2006. 1(1):63-65.

An anticancer drug, which can be used in combination with a compound ofthe present invention may, in particular, be an immunooncologytherapeutic (such as an antibody (e.g., a monoclonal antibody or apolyclonal antibody), an antibody fragment, an antibody construct (e.g.,a single-chain construct), or a modified antibody (e.g., a CDR-graftedantibody, a humanized antibody, or a “full humanized” antibody)targeting any one of CTLA-4, PD-1/PD-L1, TIM3, LAG3, OX4, CSF1R, IDO, orCD40. Such immunooncology therapeutics include, e.g., an anti-CTLA-4antibody (particularly an antagonistic or pathway-blocking anti-CTLA-4antibody; e.g., ipilimumab or tremelimumab), an anti-PD-1 antibody(particularly an antagonistic or pathway-blocking anti-PD-1 antibody;e.g., nivolumab (BMS-936558), pembrolizumab (MK-3475), pidilizumab(CT-011), AMP-224, or APE02058), an anti-PD-L1 antibody (particularly apathway-blocking anti-PD-L1 antibody; e.g., BMS-936559, MED14736,MPDL3280A (RG7446), MDX-1105, or MED16469), an anti-TIM3 antibody(particularly a pathway-blocking anti-TIM3 antibody), an anti-LAG3antibody (particularly an antagonistic or pathway-blocking anti-LAG3antibody; e.g., BMS-986016, IMP701, or IMP731), an anti-OX4 antibody(particularly an agonistic anti-OX4 antibody; e.g., MED10562), ananti-CSF1R antibody (particularly a pathway-blocking anti-CSF1Rantibody; e.g., IMC-CS4 or RG7155), an anti-IDO antibody (particularly apathway-blocking anti-IDO antibody), or an anti-CD40 antibody(particularly an agonistic anti-CD40 antibody; e.g., CP-870,893 or ChiLob 7/4). Further immunooncology therapeutics are known in the art andare described, e.g., in: Kyi C et al., FEBS Lett, 2014, 588(2):368-76;Intlekofer A M et al., J Leukoc Biol, 2013, 94(1):25-39; Callahan M K etal., J Leukoc Biol, 2013, 94(1):41-53; Ngiow S F et al., Cancer Res,2011, 71(21):6567-71; and Blattman J N et al., Science, 2004,305(5681):200-5.

It is particularly preferred that the compounds of formula (I), such asKP2299, are to be administered in combination with folinic acid (e.g.,leucovorin calcium or leucovorin sodium) and 5-fluorouracil.

A further example of a combination therapy may comprise theadministration of a compound of formula (I), including in particular onewherein R¹ and R² are joined together to form a moiety (A2) and whereinR³ and R⁴ are each —NH₃ (such as, e.g., compound 20), in combinationwith a taxane (such as, e.g., paclitaxel/taxol, nab-paclitaxel (e.g.,Abraxane®), docetaxel, larotaxel, ortataxel, or tesetaxel; preferablypaclitaxel or nab-paclitaxel; more preferably paclitaxel) and ananti-PD-1 antibody (particularly an antagonistic anti-PD-1 antibody;such as, e.g., nivolumab, pembrolizumab, pidilizumab, AMP-224, orAPE02058; preferably nivolumab). It is preferred that said compound offormula (I) is to be administered in combination with paclitaxel andnivolumab.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation. The individual componentsof such combinations may be administered either sequentially orsimultaneously/concomitantly in separate or combined pharmaceuticalformulations by any convenient route. When administration is sequential,either the compound of the present invention (i.e., the compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof) orthe further therapeutic agent(s) may be administered first.

When administration is simultaneous, the combination may be administeredeither in the same pharmaceutical composition or in differentpharmaceutical compositions. When combined in the same formulation, itwill be appreciated that the two or more compounds must be stable andcompatible with each other and the other components of the formulation.When formulated separately, they may be provided in any convenientformulation.

The compounds of formula (I) can also be administered in combinationwith physical therapy, such as radiotherapy. Radiotherapy may commencebefore, after, or simultaneously with administration of the compounds ofthe invention. For example, radiotherapy may commence 1-10 minutes, 1-10hours or 24-72 hours after administration of the compounds. Yet, thesetime frames are not to be construed as limiting. The subject is exposedto radiation, preferably gamma radiation, whereby the radiation may beprovided in a single dose or in multiple doses that are administeredover several hours, days and/or weeks. Gamma radiation may be deliveredaccording to standard radiotherapeutic protocols using standard dosagesand regimens.

The present invention thus relates to a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition comprising any of the aforementioned entities in combinationwith a pharmaceutically acceptable excipient, for use in the treatmentor prevention of cancer, wherein the compound or the pharmaceuticalcomposition is to be administered in combination with one or moreanticancer drugs and/or in combination with radiotherapy and/orimmunotherapy.

Yet, the compounds of formula (I) can also be used in monotherapy,particularly in the monotherapeutic treatment or prevention of cancer(i.e., without administering any other anticancer agents until thetreatment with the compound(s) of formula (I) is terminated).Accordingly, the invention also relates to a compound of formula (I) ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition comprising any of the aforementioned entitiesin combination with a pharmaceutically acceptable excipient, for use inthe monotherapeutic treatment or prevention of cancer.

The subject or patient to be treated in accordance with the presentinvention may be an animal (e.g., a non-human animal), a vertebrateanimal, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, or amouse), a canine (e.g., a dog), a feline (e.g., a cat), a porcine (e.g.,a pig), an equine (e.g., a horse), a primate or a simian (e.g., a monkeyor an ape, such as a marmoset, a baboon, a gorilla, a chimpanzee, anorangutan, or a gibbon), or a human. In accordance with the presentinvention, it is envisaged that animals are to be treated which areeconomically, agronomically or scientifically important. Scientificallyimportant organisms include, but are not limited to, mice, rats, andrabbits. Lower organisms such as, e.g., fruit flies like Drosophilamelagonaster and nematodes like Caenorhabditis elegans may also be usedin scientific approaches. Non-limiting examples of agronomicallyimportant animals are sheep, cattle and pigs, while, for example, catsand dogs may be considered as economically important animals.Preferably, the subject/patient is a mammal. More preferably, thesubject/patient is a human or a non-human mammal (such as, e.g., aguinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse,a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, anorangutan, a gibbon, a sheep, a cattle, or a pig). Most preferably, thesubject/patient is a human. The subject/patient to be treated inaccordance with the invention may be female or male. In a particularaspect, the present invention relates to the treatment of a femalesubject/patient, preferably a female animal (e.g., a female of any oneof the species mentioned in this paragraph), more preferably a femalehuman or a female non-human mammal, and even more preferably a femalehuman.

The term “treatment” of a disorder or disease as used herein (e.g.,“treatment” of cancer) is well known in the art. “Treatment” of adisorder or disease implies that a disorder or disease is suspected orhas been diagnosed in a patient/subject. A patient/subject suspected ofsuffering from a disorder or disease typically shows specific clinicaland/or pathological symptoms which a skilled person can easily attributeto a specific pathological condition (i.e., diagnose a disorder ordisease).

The “treatment” of a disorder or disease may, for example, lead to ahalt in the progression of the disorder or disease (e.g., nodeterioration of symptoms) or a delay in the progression of the disorderor disease (in case the halt in progression is of a transient natureonly). The “treatment” of a disorder or disease may also lead to apartial response (e.g., amelioration of symptoms) or complete response(e.g., disappearance of symptoms) of the subject/patient suffering fromthe disorder or disease. Accordingly, the “treatment” of a disorder ordisease may also refer to an amelioration of the disorder or disease,which may, e.g., lead to a halt in the progression of the disorder ordisease or a delay in the progression of the disorder or disease. Such apartial or complete response may be followed by a relapse. It is to beunderstood that a subject/patient may experience a broad range ofresponses to a treatment (such as the exemplary responses as describedherein above). The treatment of a disorder or disease may, inter alia,comprise curative treatment (preferably leading to a complete responseand eventually to healing of the disorder or disease) and palliativetreatment (including symptomatic relief).

The term “prevention” of a disorder or disease as used herein (e.g.,“prevention” of cancer) is also well known in the art. For example, apatient/subject suspected of being prone to suffer from a disorder ordisease may particularly benefit from a prevention of the disorder ordisease. The subject/patient may have a susceptibility or predispositionfor a disorder or disease, including but not limited to hereditarypredisposition. Such a predisposition can be determined by standardmethods or assays, using, e.g., genetic markers or phenotypicindicators. It is to be understood that a disorder or disease to beprevented in accordance with the present invention has not beendiagnosed or cannot be diagnosed in the patient/subject (for example,the patient/subject does not show any clinical or pathologicalsymptoms). Thus, the term “prevention” comprises the use of a compoundof the present invention before any clinical and/or pathologicalsymptoms are diagnosed or determined or can be diagnosed or determinedby the attending physician.

It is to be understood that the present invention specifically relatesto each and every combination of features and embodiments describedherein, including any combination of general and/or preferredfeatures/embodiments. In particular, the invention specifically relatesto each combination of meanings (including general and/or preferredmeanings) for the various groups and variables comprised in formula (I).

In this specification, a number of documents including patentapplications, scientific literature and manufacturers' manuals arecited. The disclosure of these documents, while not considered relevantfor the patentability of this invention, is herewith incorporated byreference in its entirety. More specifically, all referenced documentsare incorporated by reference to the same extent as if each individualdocument was specifically and individually indicated to be incorporatedby reference.

The reference in this specification to any prior publication (orinformation derived therefrom) is not and should not be taken as anacknowledgment or admission or any form of suggestion that thecorresponding prior publication (or the information derived therefrom)forms part of the common general knowledge in the technical field towhich the present specification relates.

The present invention particularly relates to the following items:

-   1. A compound of the following formula (I)

-   -   wherein:        -   R¹ and R² are joined together to form a moiety (A1), (A2) or            (A3):

-   -   -   R³ and R⁴ are joined together to form a moiety (1), or R³ is            a moiety (B2) and R⁴ is —NH₃, or R³ and R⁴ are each —NH₃:

-   -   -   R⁵ is —N(R⁵¹)— or —CH₂—;        -   R⁵¹ is hydrogen or C₁₋₈ alkyl;        -   R⁶ is C₁₋₈ alkylene, wherein one or two —CH₂— units            comprised in said C₁₋₈ alkylene are each optionally replaced            by a group independently selected from —O—, —CO—, —C(═O)O—,            —O—C(═O)—, —N(R⁶¹)—, —N(R⁶¹)—CO—, —CO—N(R⁶¹)—, arylene, and            heteroarylene, wherein said arylene and said heteroarylene            are each optionally substituted with one or more groups R⁶²;        -   each R⁶¹ is independently selected from hydrogen and C₁₋₈            alkyl;        -   each R⁶² is independently selected from C₁₋₈ alkyl, C₂₋₈            alkenyl, C₂₋₈ alkynyl, —(C₀₋₃ alkylene)-OH, —(C₀₋₃            alkylene)-O(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-SH, —(C₀₋₃            alkylene)-S(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH₂, —(C₀₋₃            alkylene)-NH(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈            alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-halogen, —(C₀₋₃            alkylene)-(C₁₋₈ haloalkyl), —(C₀₋₃ alkylene)-CF₃, —(C₀₋₃            alkylene)-CN, —(C₀₋₃ alkylene)-CHO, —(C₀₋₃            alkylene)-CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-COOH, —(C₀₋₃            alkylene)-CO—O—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-O—CO—(C₁₋₈            alkyl), —(C₀₋₃ alkylene)-CO—NH₂, —(C₀₋₃ alkylene)-CO—NH(C₁₋₈            alkyl), —(C₀₋₃ alkylene)-CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl),            —(C₀₋₃ alkylene)-NH—CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈            alkyl)-CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-SO₂—NH₂, —(C₀₋₃            alkylene)-SO₂—NH(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-SO₂—N(C₁₋₈            alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—SO₂—(C₁₋₈ alkyl),            and —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-SO₂—(C₁₋₈ alkyl);        -   R⁷ is selected from hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈            alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,            —O—(C₁₋₈ alkyl), —O—(C₂₋₈ alkenyl), —O—(C₂₋₈ alkynyl),            —O-cycloalkyl, —O-heterocycloalkyl, —O-aryl, —O-heteroaryl,            —N(R⁷¹)—(C₁₋₈ alkyl), —N(R⁷¹)—(C₂₋₈ alkenyl), —N(R⁷¹)—(C₂₋₈            alkynyl), —N(R⁷¹)-cycloalkyl, —N(R⁷¹)-heterocycloalkyl,            —N(R⁷¹)-aryl, and —N(R⁷¹)-heteroaryl, wherein said C₁₋₈            alkyl or the C₁₋₈ alkyl moiety comprised in any of the            aforementioned groups, said C₂₋₈ alkenyl or the C₂₋₈ alkenyl            moiety comprised in any of the aforementioned groups, and            said C₂₋₈ alkynyl or the C₂₋₈ alkynyl moiety comprised in            any of the aforementioned groups are each optionally            substituted with one or more groups R⁷², and further wherein            said cycloalkyl or the cycloalkyl moiety comprised in any of            the aforementioned groups, said heterocycloalkyl or the            heterocycloalkyl moiety comprised in any of the            aforementioned groups, said aryl or the aryl moiety            comprised in any of the aforementioned groups, and said            heteroaryl or the heteroaryl moiety comprised in any of the            aforementioned groups are each optionally substituted with            one or more groups R⁷³;        -   each R⁷¹ is independently selected from hydrogen and C₁₋₈            alkyl;        -   each R⁷² is independently selected from —OH, —O(C₁₋₈ alkyl),            —SH, —S(C₁₋₈ alkyl), —NH₂, —NH(C₁₋₈ alkyl), —N(C₁₋₈            alkyl)(C₁₋₈ alkyl), halogen, C₁₋₈ haloalkyl, —CF₃, —CN,            —CHO, —CO—(C₁₋₈ alkyl), —COOH, —CO—O—(C₁₋₈ alkyl),            —O—CO—(C₁₋₈ alkyl), —CO—NH₂, —CO—NH(C₁₋₈ alkyl), —CO—N(C₁₋₈            alkyl)(C₁₋₈ alkyl), —NH—CO—(C₁₋₈ alkyl), —N(C₁₋₈            alkyl)-CO—(C₁₋₈ alkyl), —SO₂—NH₂, —SO₂—NH(C₁₋₈ alkyl),            —SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—SO₂—(C₁₋₈ alkyl), and            —N(C₁₋₈ alkyl)-SO₂—(C₁₋₈alkyl);        -   each R⁷³ is independently selected from C₁₋₈ alkyl, C₂₋₈            alkenyl, C₂₋₈ alkynyl, —(C₀₋₃ alkylene)-OH, —(C₀₋₃            alkylene)-O(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-SH, —(C₀₋₃            alkylene)-S(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH₂, —(C₀₋₃            alkylene)-NH(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈            alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-halogen, —(C₀₋₃            alkylene)-(C₁₋₈ haloalkyl), —(C₀₋₃ alkylene)-CF₃, —(C₀₋₃            alkylene)-CN, —(C₀₋₃ alkylene)-CHO, —(C₀₋₃            alkylene)-CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-COOH, —(C₀₋₃            alkylene)-CO—O—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-O—CO—(C₁₋₈            alkyl), —(C₀₋₃ alkylene)-CO—NH₂, —(C₀₋₃ alkylene)-CO—NH(C₁₋₈            alkyl), —(C₀₋₃ alkylene)-CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl),            —(C₀₋₃ alkylene)-NH—CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈            alkyl)-CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-SO₂—NH₂, —(C₀₋₃            alkylene)-SO₂—NH(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-SO₂—N(C₁₋₈            alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—SO₂—(C₁₋₈ alkyl),            and —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-SO₂—(C₁₋₈ alkyl);        -   each R⁸ is independently selected from C₁₋₈ alkyl, C₂₋₈            alkenyl, C₂₋₈ alkynyl, —OH, —O—(C₁₋₈ alkyl), —SH, —S—(C₁₋₈            alkyl), —NH₂, —NH(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl),            halogen, C₁₋₈ haloalkyl, —CF₃, —CN, —CHO, —CO—(C₁₋₈ alkyl),            —COOH, —CO—O—(C₁₋₈ alkyl), —O—CO—(C₁₋₈ alkyl), —CO—NH₂,            —CO—NH(C₁₋₈ alkyl), —CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl),            —NH—CO—(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl),            —SO₂—NH₂, —SO₂—NH(C₀₋₈ alkyl), —SO₂—N(C₁₋₈ alkyl)(C₁₋₈            alkyl), —NH—SO₂—(C₁₋₈ alkyl), and —N(C₁₋₈            alkyl)-SO₂—(C₁₋₈alkyl);        -   each R⁹ is independently selected from C₁₋₈ alkyl, C₂₋₈            alkenyl, C₂₋₈ alkynyl, —OH, —O—(C₁₋₈ alkyl), —SH, —S—(C₁₋₈            alkyl), —NH₂, —NH(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl),            halogen, C₁₋₈ haloalkyl, —CF₃, —CN, —CHO, —CO—(C₁₋₈ alkyl),            —COOH, —CO—O—(C₁₋₈ alkyl), —O—CO—(C₁₋₈ alkyl), —CO—NH₂,            —CO—NH(C₁₋₈ alkyl), —CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl),            —NH—CO—(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl),            —SO₂—NH₂, —SO₂—NH(C₁₋₈ alkyl), —SO₂—N(C₁₋₈ alkyl)(C₁₋₈            alkyl), —NH—SO₂—(C₁₋₈ alkyl), and —N(C₁₋₈            alkyl)-SO₂—(C₁₋₈alkyl);        -   n is an integer of 0 to 8; and        -   m is an integer of 0 to 6;

    -   or a pharmaceutically acceptable salt or solvate thereof.

-   2. The compound of item 1, wherein R¹ and R² are joined together to    form a moiety (A1).

-   3. The compound of item 1 or 2, wherein R³ and R⁴ are joined    together to form a moiety (E1).

-   4. The compound of any one of items 1 to 3, wherein R⁵ is —NH—,    —N(—CH₃)— or —N(—CH₂CH₃)—

-   5. The compound of any one of items 1 to 4, wherein R⁶ is C₁₋₈    alkylene.

-   6. The compound of any one of items 1 to 5, wherein R⁶ is selected    from —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, and —(CH₂)₅—.

-   7. The compound of any one of items 1 to 6, wherein R⁷ is selected    from C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl.

-   8. The compound of any one of items 1 to 7, wherein R⁷ is C₁₋₅    alkyl.

-   9. The compound of any one of items 1 to 8, wherein n and m are each    0.

-   10. The compound of any one of items 1 to 9, wherein R¹ and R² are    joined together to form a moiety (A1), and wherein R³ and R⁴ are    joined together to form a moiety (E1).

-   11. The compound of item 1 or any one of its dependent items 3 to 9,    wherein R¹ and R² are joined together to form a moiety (A2), and    wherein R³ and R⁴ are each —NH₃.

-   12. The compound of item 1, which is a compound having any one of    the following formulae:

-   -   or a pharmaceutically acceptable salt or solvate thereof.

-   13. The compound of item 1, which is a compound having the following    formula:

-   -   or a pharmaceutically acceptable salt or solvate thereof.

-   14. The compound of item 1, which is a compound having the following    formula:

-   -   or a pharmaceutically acceptable salt or solvate thereof.

-   15. The compound of item 1, which is a compound having the following    formula:

or a pharmaceutically acceptable salt or solvate thereof.

-   16. A pharmaceutical composition comprising the compound of any one    of items 1 to 15 and a pharmaceutically acceptable excipient.-   17. The compound of any one of items 1 to 15 or the pharmaceutical    composition of item 16 for use as a medicament.-   18. The compound of any one of items 1 to 15 or the pharmaceutical    composition of item 16 for use in the treatment or prevention of    cancer.-   19. The compound for use according to item 18 or the pharmaceutical    composition for use according to item 18, wherein the cancer is    selected from gastrointestinal cancer, colorectal cancer, colon    cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer,    biliary tract cancer, stomach cancer, genitourinary cancer, bladder    cancer, testicular cancer, cervical cancer, malignant mesothelioma,    osteogenic sarcoma, esophageal cancer, laryngeal cancer, prostate    cancer, hormone-refractory prostate cancer, lung cancer, small cell    lung cancer, non-small cell lung cancer, breast cancer,    triple-negative breast cancer, breast cancer having a BRCA1 and/or    BRCA2 gene mutation, hematological cancer, leukemia, acute    lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic    leukemia, chronic myeloid leukemia, lymphoma, Hodgkin lymphoma,    non-Hodgkin lymphoma, follicular lymphoma, diffuse large B-cell    lymphoma, ovarian cancer, brain cancer, neuroblastoma, Ewing's    sarcoma, kidney cancer, epidermoid cancer, skin cancer, melanoma,    head and/or neck cancer, head and neck squamous cell carcinoma, and    mouth cancer.-   20. The compound for use according to item 18 or 19 or the    pharmaceutical composition for use according to item 18 or 19,    wherein the cancer is selected from colorectal cancer, colon cancer,    pancreatic cancer, lung cancer, non-small cell lung cancer, ovarian    cancer, bladder cancer, cervical cancer, malignant mesothelioma,    melanoma, head and/or neck cancer, head and neck squamous cell    carcinoma, and testicular cancer.-   21. The compound for use according to any one of items 18 to 20 or    the pharmaceutical composition for use according to any one of items    18 to 20, wherein the cancer is selected from colorectal cancer,    colon cancer, pancreatic cancer, lung cancer, non-small cell lung    cancer, ovarian cancer, cervical cancer, melanoma, head and/or neck    cancer, and head and neck squamous cell carcinoma.-   22. The compound for use according to any one of items 18 to 21 or    the pharmaceutical composition for use according to any one of items    18 to 21, wherein the cancer is colorectal cancer, colon cancer or    pancreatic cancer.-   23. The compound for use according to any one of items 18 to 22 or    the pharmaceutical composition for use according to any one of items    18 to 22, wherein the compound or the pharmaceutical composition is    to be administered in combination with an anticancer drug and/or in    combination with radiotherapy and/or immunotherapy.-   24. Use of the compound of any one of items 1 to 15 in the    preparation of a medicament for the treatment or prevention of    cancer.-   25. The use of item 24, wherein the cancer is selected from    gastrointestinal cancer, colorectal cancer, colon cancer, liver    cancer, hepatocellular carcinoma, pancreatic cancer, biliary tract    cancer, stomach cancer, genitourinary cancer, bladder cancer,    testicular cancer, cervical cancer, malignant mesothelioma,    osteogenic sarcoma, esophageal cancer, laryngeal cancer, prostate    cancer, hormone-refractory prostate cancer, lung cancer, small cell    lung cancer, non-small cell lung cancer, breast cancer,    triple-negative breast cancer, breast cancer having a BRCA1 and/or    BRCA2 gene mutation, hematological cancer, leukemia, acute    lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic    leukemia, chronic myeloid leukemia, lymphoma, Hodgkin lymphoma,    non-Hodgkin lymphoma, follicular lymphoma, diffuse large B-cell    lymphoma, ovarian cancer, brain cancer, neuroblastoma, Ewing's    sarcoma, kidney cancer, epidermoid cancer, skin cancer, melanoma,    head and/or neck cancer, head and neck squamous cell carcinoma, and    mouth cancer.-   26. The use of item 24 or 25, wherein the cancer is selected from    colorectal cancer, colon cancer, pancreatic cancer, lung cancer,    non-small cell lung cancer, ovarian cancer, bladder cancer, cervical    cancer, malignant mesothelioma, melanoma, head and/or neck cancer,    head and neck squamous cell carcinoma, and testicular cancer.-   27. The use of any one of items 24 to 26, wherein the cancer is    selected from colorectal cancer, colon cancer, pancreatic cancer,    lung cancer, non-small cell lung cancer, ovarian cancer, cervical    cancer, melanoma, head and/or neck cancer, and head and neck    squamous cell carcinoma.-   28. The use of any one of items 24 to 27, wherein the cancer is    colorectal cancer, colon cancer or pancreatic cancer.-   29. The use of any one of items 24 to 28, wherein the medicament is    for administration in combination with an anticancer drug and/or in    combination with radiotherapy and/or immunotherapy.-   30. A method of treating cancer, the method comprising administering    the compound of item 1 to a subject in need thereof.-   31. The method of item 30, wherein the cancer is selected from    gastrointestinal cancer, colorectal cancer, colon cancer, liver    cancer, hepatocellular carcinoma, pancreatic cancer, biliary tract    cancer, stomach cancer, genitourinary cancer, bladder cancer,    testicular cancer, cervical cancer, malignant mesothelioma,    osteogenic sarcoma, esophageal cancer, laryngeal cancer, prostate    cancer, hormone-refractory prostate cancer, lung cancer, small cell    lung cancer, non-small cell lung cancer, breast cancer,    triple-negative breast cancer, breast cancer having a BRCA1 and/or    BRCA2 gene mutation, hematological cancer, leukemia, acute    lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic    leukemia, chronic myeloid leukemia, lymphoma, Hodgkin lymphoma,    non-Hodgkin lymphoma, follicular lymphoma, diffuse large B-cell    lymphoma, ovarian cancer, brain cancer, neuroblastoma, Ewing's    sarcoma, kidney cancer, epidermoid cancer, skin cancer, melanoma,    head and/or neck cancer, head and neck squamous cell carcinoma, and    mouth cancer.-   32. The method of item 30, wherein the cancer is selected from    colorectal cancer, colon cancer, pancreatic cancer, lung cancer,    non-small cell lung cancer, ovarian cancer, bladder cancer, cervical    cancer, malignant mesothelioma, melanoma, head and/or neck cancer,    head and neck squamous cell carcinoma, and testicular cancer.-   33. The method of item 30, wherein the cancer is selected from    colorectal cancer, colon cancer, pancreatic cancer, lung cancer,    non-small cell lung cancer, ovarian cancer, cervical cancer,    melanoma, head and/or neck cancer, and head and neck squamous cell    carcinoma.-   34. The method of item 30, wherein the cancer is colorectal cancer,    colon cancer or pancreatic cancer.-   35. The method of item 30, wherein the method comprises    administering the compound in combination with an anticancer drug    and/or in combination with radiotherapy and/or immunotherapy.-   36. The method of item 30, wherein the subject is a human.

In a further aspect, the invention relates to the compound KP2260 (asdepicted in Example 1) or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition comprising any of theaforementioned entities in combination with a pharmaceuticallyacceptable excipient. In this aspect, the invention also relates toKP2260 or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition comprising any of the aforementioned entitiesand a pharmaceutically acceptable excipient, for use as a medicament,particularly for use in the treatment or prevention of cancer (includingany of the specific cancers described herein in connection with thecompound of formula (I)).

The invention is also described by the following illustrative figures.The appended figures show:

FIGS. 1A-G: Superior anticancer activity of KP2299 against CT-26 coloncancer cells in vivo. KP2299 is compared against (FIG. 1A) oxaliplatin,(FIG. 1B) the oxaliplatin-releasing bismaleimide platinum(IV) drugKP2156 and (FIG. 1C) the oxaliplatin-releasing monomaleimide analogueKP2260. Data in FIGS. 1A-C are pooled from several independentexperiments. (FIG. 1D) shows data from an experiment regarding acomparison of the cisplatin-releasing monomaleimide analogue KP2372 withcisplatin. (FIG. 1E) and (FIG. 1F) show data from an experimentregarding a comparison of the cisplatin-releasing monomaleimide complexKP2540 and the oxaliplatin-derivate KP2541 (without NH-group in thelinker). (FIG. 1G) shows data from one experiment regarding KP2552 (witha 4-methyl-1,2-cyclohexanediamine ligand) and the carboplatin-releasingcomplex KP2551 in comparison to carboplatin. All experiments have beenperformed in male Balb/c mice and the control (0.9% NaCl) was treatedaccording to the KP2299 and KP2156 solvent.

FIGS. 2A-D: Impact of gender on the anticancer activity of KP2299against CT-26 colon cancer cells in vivo. (FIG. 2A) and (FIG. 2B) showtumor burden and survival, respectively, in male animals, while in (FIG.2C) and (FIG. 2D) data from female mice is shown. In (FIG. 2A) and (FIG.2B) control mice were treated according to the KP2299 solvent (0.9%NaCl) and in (FIG. 2C) and (FIG. 2D) the control group was treated with5% glucose according to the oxaliplatin solvent.

FIG. 3 : Superior anticancer activity of KP2299 against B16 melanomacells in vivo. KP2299 is compared against oxaliplatin in male C57/B6JRjmice and the control was treated according to the KP2299 solvent (0.9%NaCl).

FIG. 4 : Anticancer activity of KP2299, oxaliplatin, KP2372 andcisplatin against leukemic L1210 cells in vivo. The figure shows datapooled together from several independent experiments.

FIG. 5 : Hydrolytic stability of KP2299 in buffered aqueous solution atdifferent pH values determined by RP-HPLC.

The invention will now be described by reference to the followingexamples, which are merely illustrative and are not to be construed as alimitation of the scope of the present invention.

EXAMPLES

The compounds described in this section are defined by their chemicalformulae and their corresponding chemical names. In case of conflictbetween any chemical formula and the corresponding chemical nameindicated herein, the present invention relates to both the compounddefined by the chemical formula and the compound defined by the chemicalname, and particularly relates to the compound defined by the chemicalformula.

Example 1: Synthesis of Monomaleimide-Functionalized Platinum Compounds

Materials and Methods:

Potassium tetrachloridoplatinate (K₂PtCl₄) was purchased from JohnsonMatthey (Switzerland). Water for synthesis was taken from a reverseosmosis system and distilled twice before use. For HPLC Milli-Q water(18.2 MΩ·cm, Merck Milli-Q Advantage, Darmstadt, Germany) was used.Other chemicals and solvents were purchased from commercial suppliers(Sigma Aldrich, Acros, Fluka and Fisher Scientific). The platinum(II)precursors cisplatin (1), oxaliplatin (2),(SP-4-2)-diamminediiodidoplatinum(II),(SP-4-3)-[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]oxalatoplatinum(II)(25) and carboplatin (28) were prepared according to literature-knownprocedures (cisplatin and (SP-4-2)-diamminediiodidoplatinum(II): Dhara,S. Ch. Indian J. Chem. 1970, 8(2), 193-194, oxaliplatin: Kidani, Y;Inagaki, K. J. Med. Chem. 1978, 21(12), 1315-1318, carboplatin: Rochon,F. D.; Gruia, L. M. Inorg. Chim. Acta 2000, 306, 193-204 and(SP-4-3)-[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]oxalatoplatinum(II):Abramkin, S. A.; Jungwirth, U.; Valiahdi, S. M.; Dworak, C.; Habala, L.;Meelich, K.; Berger, W.; Jakupec, M. A.; Hartinger, C. G.; Nazarov, A.A.; Galanski, M.; Keppler, B. K. J. Med. Chem. 2010, 53, 7356-7364).Thereafter, these were oxidized with hydrogen peroxide (50%) usingeither methanol (Dunham, S. O.; Larsen, R. D. Inorg. Chem. 1993, 32,2049-2055) or acetic acid (Lee, Y.-A.; Jung, S. M.; Kang, S. W.; Jung,O.-S. Transition Met. Chem. 2004, 29, 710-713) as a solvent to yield theunsymmetrically oxidized platinum(IV) precursors 3-6, 26, 27 and 29. Themaleimide- and succinimide-functionalized isocyanate ligands wereprepared according to a recently published procedure (Pichler, V.; Mayr,J.; Heffeter, P.; Dömötör, O.; Enyedy, É. A.; Hermann, G.; Groza, D.;Kölensperger, G.; Galanski, M.; Berger, W.; Keppler, B. K.; Kowol, C. R.Chem. Commun. 2013, 49, 2049-2051) and the mixed anhydride ligandsaccording to literature-known procedure (Cheronis, J. C.; Whalley, E.T.; Nguyen, K. T.; Eubanks, S. R.; Allen, L. G.; Duggan, M. J.; Loy, S.D.; Bonham, K. A.; Blodgett, J. K. J. Med. Chem. 1992, 35, 1563-1572).Compounds 7-14, 17-20, 22-24 and 30-31 were purified by preparativeRP-HPLC using a Waters XBridge C18 column on an Agilent 1200 Seriessystem. Milli-Q water, containing 0.1% formic acid and methanol oracetonitrile were used as eluents. Electrospray ionization (ESI) massspectra were recorded on a Bruker amaZon SL ion trap mass spectrometerin positive and/or negative mode by direct infusion. High resolutionmass spectra were measured on a Bruker maXis™ UHR ESI time of flightmass spectrometer. All mass spectra were recorded at the MassSpectrometry Centre of the University of Vienna. ¹H-, ¹³C-, ¹⁵N-, and¹⁹⁵Pt-one- and two-dimensional NMR spectra were recorded on a BrukerAvance III 500 MHz spectrometer at 500.10 (¹H), 127.75 (¹³C), 50.68(¹⁵N), and 107.51 (¹⁹⁵Pt) MHz at 298 K. For ¹H- and ¹³C-NMR spectra thesolvent residual peak was taken as internal reference, whereas¹⁹⁵Pt-shifts were referenced relative to external K₂PtCl₄ and ¹⁵N-shiftsrelative to external NH₄Cl. Elemental analysis measurements wereperformed on a Perkin Elmer 2400 CHN Elemental Analyzer at theMicroanalytical Laboratory of the University of Vienna.

General Procedure for the Synthesis of Compounds 7-14, 17-20, 22-24 and30-31

The unsymmetrically, oxidized platinum(IV) compound and thecorresponding isocyanate (in the case of compounds 7-14, 17-20, 23-24and 30-31) or the corresponding mixed anhydride (in case of compound 22)were transferred into a Schlenk tube and set under argon atmosphere.After the addition of dry DMF, the suspension was stirred overnight.Remaining precipitates were filtered off, before the DMF was removedunder reduced pressure. The remains were taken up as a suspension inmethanol and fully precipitated by addition of diethyl ether. After afew hours in the fridge, the crude product was filtered off, washed withdiethyl ether and dried under reduced pressure. The crude product wastaken up in water and filtered before it was purified by preparativeRP-HPLC. Collected product fractions were lyophilized and dried invacuo.

(OC-6-44)-Diamminedichloridomethoxido[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV)(7; KP2298)

The compound was synthesized from(OC-6-44)-diamminedichloridohydroxidomethoxidoplatinum(IV) (3; 140 mg,0.40 mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (2 eq., 134mg, 0.80 mmol) in 3 mL DMF (abs.). Purification via preparative RP-HPLC,isocratic with 8% methanol, yielded a pale yellow solid. Yield: 70.5 mg(18%); ¹H-NMR (DMSO-d6): δ=6.98 (s, 2H, CH), 6.38 (s, 1H, NH), 6.17-5.73(m, 6H, NH₃), 3.46-3.36 (m, 2H, NCH₂), 3.06-2.96 (m, 2H, NHCH₂), 2.63(br, 3H, CH₃) ppm; ¹³C-NMR (DMSO-d6): δ=171.1 (COCH), 164.8 (CONH),134.5 (CH), 60.5 (CH₃), 39.2 (NHCH₂), 37.5 (NCH₂) ppm; ¹⁵N{¹H}-NMR(DMSO-d6): δ=59.5 (NH), −31.7 (NH₃) ppm; ¹⁹⁵Pt-NMR (DMSO-d6): δ=2642(major), 2629 (minor) ppm; HRMS (ESI-TOF): calcd. for[C₈H₁₈Cl₂N₄O₅Pt—Na⁺]⁺: 536.0043, found: 536.0028; elemental analysiscalcd. for C₈H₁₈Cl₂N₄O₅Pt.0.5H₂O: C: 18.36, H: 3.27, N: 10.71, O: 16.82,found: C: 18.38, H: 2.92, N: 10.32, O: 16.57.

(OC-6-44)-Acetatodiamminedichlorido[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV)(8; KP2372)

The compound was synthesized from(OC-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV) (4; 450 mg,1.20 mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (2 eq., 398mg, 2.39 mmol) in 5 mL DMF (abs.). Purification via preparative RP-HPLC,isocratic with 3% methanol, yielded a pale yellow solid. Yield: 267.0 mg(42%); ¹H-NMR (DMSO-d6): δ=6.98 (s, 2H, CH), 6.80-6.37 (m, 6H, NH₃),6.67 (br, 1H, NH), 3.45-3.37 (m, 2H, NCH₂), 3.07-2.99 (m, 2H, NHCH₂),1.90 (s, 3H, CH₃) ppm; ¹³C-NMR (DMSO-d6): δ=178.2 (COCH₃), 171.1 (COCH),163.8 (CONH), 134.5 (CH), 38.9 (NHCH₂), 37.4 (NCH₂), 22.8 (CH₃) ppm;¹⁵N{¹H}-NMR (DMSO-d6): δ=59.2 (NH), −39.4 (NH₃) ppm; ¹⁹⁵Pt-NMR(DMSO-d6): δ=2880 (major), 2860 (minor) ppm; HRMS (ESI-TOF): calcd. for[C₉H₁₈Cl₂N₄O₆Pt—Na⁺]⁺: 564.9944, found: 564.9977; elemental analysiscalcd. for C₉H₁₈Cl₂N₄O₆Pt-1.5H₂O: C: 18.99, H: 3.36, N: 9.84, found: C:18.73, H: 3.18, N: 9.70.

(OC-6-44)-Diamminedichloridomethoxido[2-(2,5-dioxopyrrolidin-1-yl)ethyl)carbamato]platinum(IV)(9)

The compound was synthesized from(OC-6-44)-diamminedichloridohydroxidomethoxidoplatinum(IV) (3; 200 mg,0.57 mmol) and 1-(2-isocyanatoethyl)pyrrolidine-2,5-dione (1.5 eq., 145mg, 0.86 mmol) in 3 mL DMF (abs.). Purification via preparative RP-HPLC,isocratic with 5% methanol, yielded a pale yellow solid. Yield: 124.2 mg(42%); ¹H-NMR (DMSO-d6): δ=6.32 (s, 1H, NH), 6.20-5.70 (m, 6H, NH₃),3.47-3.29 (m, 2H, NCH₂), 3.10-2.92 (m, 2H, NHCH₂), 2.63 (br, 3H, CH₃),2.58 (br, 4H, COCH₂) ppm; ¹³C-NMR (DMSO-d6): δ=177.9 (COCH₂), 164.9(CONH), 60.5 (CH₃), 38.3 (br, NHCH₂, NCH₂), 28.1 (COCH2) ppm; ¹⁹⁵Pt-NMR(DMSO-d6): δ=2642 (major), 2629 (minor) ppm; HRMS (ESI-TOF): calcd. for[C₈H₁₈Cl₂N₄O₅Pt—Na⁺]⁺: 538.0200, found: 538.0195; elemental analysiscalcd. for C₈H₁₈Cl₂N₄O₅Pt.0.5H₂O: C: 18.32, H: 3.65, N: 10.69, found: C:18.73, H: 3.66, N: 10.22.

(OC-6-44)-Acetatodiamminedichlorido[2-(2,5-dioxopyrrolidin-1-yl)ethyl)carbamato]platinum(IV)(10)

The compound was synthesized from(OC-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV) (4; 600 mg,1.60 mmol) and 1-(2-isocyanatoethyl)pyrrolidine-2,5-dione (1.5 eq., 402mg, 2.39 mmol) in 5 mL DMF (abs.). Purification via preparative RP-HPLC,with a gradient from 5-10.5% methanol in 10 min, yielded a pale yellowsolid. Yield: 232.2 mg (27%); ¹H-NMR (DMSO-d6): δ=6.89-6.33 (m, 7H, NH₃,NH), 3.41-3.34 (m, 2H, NCH₂), 3.03 (q, J=6.2 Hz, 2H, NHCH₂), 2.59 (br,4H, COCH₂), 1.90 (s, 3H, CH₃) ppm; ¹³C-NMR (DMSO-d6): δ=178.2 (COCH₃),177.8 (COCH₂), 163.9 (CONH), 38.2 (NHCH₂, NCH₂), 28.1 (COCH₂), 22.8(CH₃) ppm; ¹⁹⁵Pt-NMR (DMSO-d6): δ=2880 (major), 2859 (minor) ppm; HRMS(ESI-TOF): calcd. for [CH₁₈Cl₂N₄O₆Pt—Na⁺]⁺: 567.0100, found: 567.0138;elemental analysis calcd. for C₉H₁₈Cl₂N₄O₆Pt.H₂O: C: 19.23, H: 3.59, N:9.96, found: C: 19.17, H: 3.35, N: 9.88.

(OC-6-34)-[(1R,2R)-Cyclohexane-1,2-diamine]methoxidooxalato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV)(11; KP2260)

The compound was synthesized from(OC-6-44)-[(1R,2R)-cyclohexane-1,2-diamine]hydroxidomethoxidooxalatoplatinum(IV)(5; 170 mg, 0.38 mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (2eq., 127 mg, 0.76 mmol) in 7 mL DMF (abs.). Purification via preparativeRP-HPLC, with a gradient from 15-35% methanol in 10 min, yielded a whitesolid. Yield: 88.7 mg (38%); ¹H-NMR (DMSO-d6): δ=9.85-9.55 (m, 1H, NH₂),8.33-8.09 (m, 1H, NH₂), 7.79-7.59 (m, 1H, NH₂), 7.07-6.83 (m, 1H, NH₂),6.98 (s, 2H, COCH), 6.44 (s, 1H, NH), 3.55-3.45 (m, 1H, NCH₂), 3.39-3.29(m, 1H, NCH₂), 3.15-3.05 (m, 1H, NHCH₂), 3.00-2.90 (m, 1H, NHCH₂),2.63-2.43 (m, 2H, CH_(dach)), 2.41 (s, 3H, CH₃), 2.19-2.07 (m, 1H,CH_(2,dach)), 2.07-1.96 (m, 1H, CH_(2,dach)), 1.60-1.42 (m, 3H,CH_(2,dach)), 1.39-1.27 (m, 1H, CH_(2,dach)), 1.25-1.07 (m, 2H,CH_(2,dach)) ppm; ¹³C-NMR (DMSO-d6): δ=171.0 (COCH), 165.2 (CONH), 163.7(CO_(ox)), 163.6 (CO_(ox)), 134.4 (COCH), 61.3 (CH_(dach)), 59.5(CH_(dach)), 57.4 (CH₃), 39.0 (NHCH₂), 37.4 (NCH₂), 30.6 (CH_(2,dach)),23.7 (CH_(2,dach)), 23.6 (CH_(2,dach)) ppm; ¹⁵N{¹H}-NMR (DMSO-d6):δ=60.9 (NH), −6.4 (NH₂), −1.5 (NH₂) ppm; ¹⁹⁵Pt-NMR (DMSO-d6): δ=3001(major), 2995 (minor) ppm; HRMS (ESI-TOF): calcd. for[C₁₆H₂₄N₄O₉Pt—Na⁺]⁺: 634.1089, found: 634.1089; elemental analysiscalcd. for C₁₆H₂₄N₄O₉Pt.H₂O: C: 30.53, H: 4.16, N: 8.90 found: C: 30.29,H: 4.08, N: 8.75.

(OC-6-34)-Acetato[(1R,2R)-cyclohexane-1,2-diamine]oxalato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV)(12, KP2299)

The compound was synthesized from(OC-6-44)-acetato[(1R,2R)-cyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV)(6; 200 mg, 0.42 mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (2eq., 140 mg, 0.85 mmol) in 2 mL DMF (abs.). Purification via preparativeRP-HPLC, isocratic with 15% methanol, yielded a white solid. Yield:111.2 mg (41%); ¹H-NMR (DMSO-d6): δ=9.63 (bs, 1H, NH₂), 8.74-8.00 (m,3H, NH₂), 6.99 (s, 2H, COCH), 6.79 (t, J=5.9 Hz, 1H, NH), 3.58-3.45 (m,1H, NCH₂), 3.42-3.29 (m, 1H, NCH₂), 3.19-3.08 (m, 1H, NHCH₂), 3.01-2.89(m, 1H, NHCH₂), 2.70-2.60 (m, 1H, CH_(dach)), 2.60-2.50 (m, 1H,CH_(dach)), 2.15 (bs, 2H, CH_(2,dach)), 1.95 (s, 1H, CH₃), 1.59-1.10 (m,6H, CH_(2,dach)) ppm; ¹³C-NMR (DMSO-d6): δ=178.4 (COCH₃), 171.0 (COCH),164.2 (CONH), 163.3 (CO_(ox)), 134.5 (COCH), 61.1 (CH_(dach)), 60.7(CH_(dach)), 39.0 (NHCH₂), 37.2 (NCH₂), 31.0 (CH_(2,dach)), 30.9(CH_(2,dach)), 23.5 (CH_(2,dach)), 23.4 (CH_(2,dach)), 22.9 (CH₃) ppm;¹⁹⁵Pt-NMR (DMSO-d6): δ=3236 (major), 3227 (minor) ppm; HRMS (ESI-TOF):calcd. for [C₁₇H₂₄N₄O₁₀Pt—Na⁺]⁺: 662.1038, found: 662.1033; elementalanalysis calcd. for C₁₇H₂₄N₄O₁₀Pt.H₂O: C: 31.05, H: 3.99, N: 8.52,found: C: 30.96, H: 3.91, N: 8.44.

(OC-6-34)-[(1R,2R)-Cyclohexane-1,2-diamine]methoxidooxalato[2-(2,5-dioxopyrrolidin-1-yl)ethyl)carbamato]platinum(IV)(13)

The compound was synthesized from(OC-6-44)-[(1R,2R)-cyclohexane-1,2-diamine]hydroxidomethoxidooxalatoplatinum(IV)(5; 200 mg, 0.45 mmol) and 1-(2-isocyanatoethyl)pyrrolidine-2,5-dione (2eq., 151 mg, 0.90 mmol) in 3 mL DMF (abs.). Purification via preparativeRP-HPLC, isocratic with 14% methanol, yielded a white solid. Yield:118.1 mg (43%); 1H-NMR (DMSO-d6): δ=9.84-9.42 (m, 1H, NH₂), 8.20 (bs,1H, NH₂), 7.70 (bs, 1H, NH₂), 6.98 (bs, 1H, NH₂), 6.43 (t, J=5.9 Hz, 1H,NH), 3.51-3.41 (m, 1H, NCH₂), 3.35-3.25 (m, 1H, NCH₂), 3.13-2.94 (m, 2H,NHCH₂), 2.62-2.55 (m, 1H, CH_(dach)), 2.58 (s, 4H, COCH₂), 2.54-2.46 (m,1H, CH_(dach)), 2.41 (s, 3H, CH₃), 2.17-2.08 (m, 1H, CH_(2,dach)),2.07-1.96 (m, 1H, CH_(2,dach)), 1.58-1.42 (m, 3H, CH_(2,dach)),1.41-1.27 (m, 1H, CH_(2,dach)), 1.22-1.08 (m, 2H, CH_(2,dach)) ppm;¹³C-NMR (DMSO-d6): δ=177.7 (COCH₂), 165.3 (CONH), 163.7 (CO_(ox)), 163.6(CO_(ox)), 61.3 (CH_(dach)), 59.5 (CH_(da)ch), 57.4 (CH₃), 38.2 (NHCH₂),38.1 (NCH₂), 30.6 (CH_(2,dach)), 28.0 (CH_(2,dach)), 23.7 (CH_(2,dach)),23.6 (CH_(2,dach)) ppm; ¹⁹⁵Pt-NMR (DMSO-d6): δ=3000 (major), 2992(minor) ppm; HRMS (ESI-TOF): calcd. for [C₁₆H₂₆N₄O₉Pt—Na⁺]⁺: 636.1245,found: 636.1249; elemental analysis calcd. for C₁₆H₂₆N₄O₉Pt.H₂O: C:30:43, H: 4:47, N: 8:87, found: C: 30:26, H: 4:59, N: 8:72.

(OC-6-34)-Acetato[(1R,2R)-cyclohexane-1,2-diamine]oxalato[2-(2,5-dioxopyrrolidin-1-yl)ethyl)carbamato]platinum(IV)(14)

The compound was synthesized from(OC-6-44)-acetato[(1R,2R)-cyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV)(6; 200 mg, 0.42 mmol) and 1-(2-isocyanatoethyl)pyrrolidine-2,5-dione(1.5 eq., 107 mg, 0.63 mmol) in 4 mL DMF (abs.). Purification viapreparative RP-HPLC, isocratic with 17% methanol, yielded a white solid.Yield: 92.2 mg (18%); ¹H-NMR (DMSO-d6): δ=9.76-9.25 (m, 1H, NH₂),8.74-8.02 (m, 3H, NH₂), 6.76 (t, J=6.0 Hz, 1H, NH), 3.53-3.42 (m, 1H,NCH₂), 3.37-3.25 (m, 1H, NCH₂), 3.14-2.95 (m, 2H, NHCH₂), 2.71-2.62 (m,1H, CH_(dach)), 2.62-2.53 (m, 1H, CH_(dach)), 2.58 (s, 4H, COCH₂), 2.14(bs, 2H, CH_(2,dach)), 1.95 (s, 1H, CH₃), 1.57-1.33 (m, 4H,CH_(2,dach)), 1.29-1.10 (m, 2H, CH_(2,dach)) ppm; ¹³C-NMR (DMSO-d6):δ=178.4 (COCH₃), 177.7 (COCH), 164.2 (CONH), 163.3 (CO_(ox)), 61.1(CH_(dach)), 60.8 (CH_(dach)), 38.1 (NHCH₂), 37.9 (NCH₂), 31.0(CH_(2,dach)), 30.9 (CH_(2,dach)), 28.0 (COCH₂), 23.5 (CH_(2,dach)),23.4 (CH_(2,dach)), 22.9 (CH₃) ppm; ¹⁹⁵Pt-NMR (DMSO-d6): δ=3236 (major),3225 (minor) ppm; HRMS (ESI-TOF): calcd. for [C₁₇H₂₆N₄O₁₀Pt—Na⁺]⁺:664.1194, found: 664.1189; elemental analysis calcd. forC₁₇H₂₆N₄O₁₀Pt-1.5H₂O: C: 30.54, H: 4.37, N: 8.38, found: C: 30.37, H:3.98, N: 8.24.

(SP-4-2)-Diammineoxalatoplatinum(II) (15)

692 mg of (SP-4-2)-diamminediiodidoplatinum(II) (1.43 mmol) weresuspended in 13 mL triple distilled water and 475 mg AgNO₃ (1.95 eq.,2.80 mmol) were added. The suspension was stirred vigorously for 8 h.Thereafter, the precipitate was filtered off, 257.6 mg potassium oxalate(0.975 eq., 1.40 mmol) were added and the reaction mixture was stirredovernight. After 1 h at 4° C., the white product was filtered off,washed with small amounts of cold triple distilled water, and dried overP₂O₅ under reduced pressure. Yield: 434.1 mg (98%).

(OC-6-44)-Acetatodiamminehydroxidooxalatoplatinum(IV) (16)

200 mg of (SP-4-2)-diammineoxalatoplatinum(II) (15) (0.63 mmol) weresuspended in 35 mL glacial acetic acid. After the addition of 715 μLH₂O₂ (50%) (20 eq., 12.61 mmol), the suspension was stirred in the darkfor 2 days. The white precipitate was filtered off, washed with glacialacetic acid and diethyl ether and dried under reduced pressure. Theproduct was used without further purification. Yield: 175 mg (71%).

(OC-6-34)-Acetatodiammineoxalato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV)(17)

The compound was synthesized from(OC-6-44)-acetatodiamminehydroxidooxalatoplatinum(IV) (16; 66.3 mg, 0.17mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (2 eq., 56.0 mg,0.34 mmol) in 5 mL DMF (abs.) according to the general procedure.Purification via preparative RP-HPLC, isocratic with 3% methanol,yielded a white solid. Yield: 17.5 mg (20%); ¹H-NMR (DMSO-d6): δ=6.99(s, 2H, CH), 6.85-6.39 (m, 6H, NH₃), 6.82 (br, 1H, NH), 3.42 (t, J=6.5Hz, 2H, NCH₂), 3.10-3.00 (m, 2H, NHCH₂), 1.92 (s, 3H, CH₃) ppm; ¹³C-NMR(DMSO-d6): δ=177.8 (COCH₃), 171.5 (COCH), 164.2 (CO_(ox)), 163.6 (CONH),135.0 (CH), 39.5 (NHCH₂), 37.9 (NCH₂), 22.8 (CH₃) ppm; ¹⁹⁵Pt-NMR(DMSO-d6): δ=3393 (major), 3383 (minor) ppm; HRMS (ESI-TOF): calcd. for[C₁₁H₁₆N₄O₁₀Pt—Na⁺]⁺: 582.0406, found: 582.0417.

(OC-6-54-A)-Acetato[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV)(26) and(OC-6-54-C)-Acetato[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV)(27)

The compound mixture was synthesized out of 51.5 mg of(SP-4-3)-[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]oxalatoplatinum(II)(25, 125.2 μmol) which was suspended in 2 mL glacial acetic acid. Afterthe addition of 71.0 μL H₂O₂ (50%) (10 eq. 1.25 mmol), the suspensionwas stirred in the dark for 16 h. The remaining solution wasconcentrated under reduced pressure and the product precipitated by theaddition of MeOH and diethyl ether. The white product was filtered off,washed with diethyl ether and dried under reduced pressure. The productwas used without further purification. Yield: 56.0 mg (92%).

Mixture of(OC-6-35-A)-Acetato[(1R,2R,4R)-4-methylcyclohexan-1,2-diamin]oxalato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platin(IV)(18) and(OC-6-35-C)-Acetato[(1R,2R,4R)-4-methylcyclohexan-1,2-diamin]oxalato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platin(IV)(19)

The compound mixture was synthesized from the racemic mixture of(OC-6-54-A/C)-acetato[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV)(26/27; 50 mg, 102.59 μmol) and1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione (3 eq., 51.1 mg, 307.78 μmol)in 1.5 mL DMF (abs.) according to the general procedure. Purificationvia preparative RP-HPLC, with a gradient from 23-33% methanol in 20 min,yielded a white solid. Yield: 16.7 mg (25%); 1H-NMR (DMSO-d6): δ=9.59(br, 1H, NH₂), 8.53 (br, 1H, NH₂), 8.30 (br, 1H, NH₂), 8.20 (br, 1H,NH₂), 7.00 (s, 2H, COCH), 6.80 (br, 1H, NH), 3.58-3.46 (m, 1H, NCH₂),3.41-3.28 (m, 1H, NCH₂), 3.19-3.09 (m, 1H, NHCH₂), 3.04-2.92 (m, 1H,NHCH₂), 2.80-2.51 (m, 2H, CH_(dach)), 2.11 (br, 2H, CH_(2,dach)), 1.96(s, 1H, CH₃), 1.60-1.37 (m, 3H, CH_(2,dach)), 1.23-1.09 (m, 1H,CH_(2,dach)), 1.04-0.86 (m, 1H, CH_(dach)), 0.95 (d, J=6.4 Hz, 3H,CH_(3,dach)) ppm; HRMS (ESI-TOF): calcd. for [C₁₈H₂₆N₄O₁₀Pt—Na⁺]⁺:676.1190, found: 676.1190; elemental analysis calcd. forC₁₈H₂₆N₄O₁₀Pt.H₂O: C: 32.63, H: 4.11, N: 8.47, found: C: 32.69, H: 4.12,N: 8.15. If desired, compounds 18 and 19 can be separated using, e.g.,chiral column chromatography (particularly chiral HPLC).

(SP-4-2)-Diamminecyclobutane-1,1-dicarboxylatoplatinum(II) (28)

1.894 g of (SP-4-2)-diamminediiodidoplatinum(II) (3.92 mmol) weresuspended in 150 mL triple distilled water and 1.198 g Ag₂SO₄ (0.98 eq.,3.84 mmol) were added. The suspension was stirred vigorously for 4 h.Thereafter, the precipitate was filtered off, a solution of 635.9 mgcyclobutane-1,1-dicarboxylic acid (1.13 eq., 4.41 mmol) and 1.213 gBa(OH)₂.8H₂O (0.98 eq., 3.84 mmol) in 50 mL triple distilled water wasadded and the reaction mixture was stirred for another hour. Afterfiltration, the solution was concentrated under reduced pressure and theproduct precipitated with MeOH. The white product was filtered off,washed with MeOH and dried under reduced pressure. Yield: 1.214 g (85%).

(OC-6-44)-acetatodiamminecyclobutane-1,1-dicarboxylatohydroxidoplatinum(IV)(29)

300 mg of (SP-4-2)-diamminecyclobutane-1,1-dicarboxylatoplatinum(II)(28) (0.81 mmol) were suspended in 7 mL glacial acetic acid. After theaddition of 458.0 μL H₂O₂ (50%) (10 eq. 8.08 mmol), the suspension wasstirred in the dark for 2 days. The remaining solution was concentratedunder reduced pressure and the product precipitated by the addition ofMeOH and diethyl ether. The white product was filtered off, washed withdiethyl ether and dried under reduced pressure. The product was usedwithout further purification. Yield: 337.2 mg (93%).

(OC-6-34)-Acetatodiamminecyclobutane-1,1-dicarboxylato[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethylcarbamato]platinum(IV)(20; KP2551)

The compound was synthesized from(OC-6-44)-acetatodiamminecyclobutane-1,1-dicarboxylatohydroxidoplatinum(IV)(29; 300.0 mg, 0.67 mmol) and 1-(2-isocyanatoethyl)-1H-pyrrole-2,5-dione(2 eq., 222.8 mg, 1.34 mmol) in 3 mL DMF (abs.) according to the generalprocedure. Purification via preparative RP-HPLC, isocratic with 7%acetonitrile, yielded a white solid. Yield: 50.6 mg (12%); ¹H-NMR(DMSO-d6): δ=6.99 (s, 2H, CH), 6.71-6.24 (m, 6H, NH₃), 6.62 (br, 1H,NH), 3.42 (t, J=6.4 Hz, 2H, NCH₂), 3.05 (q, J=6.4 Hz, 2H, NHCH₂), 2.49(t, J=8.0 Hz, 4H, CH₂CCH₂), 1.90 (s, 3H, CH₃), 1.81 (quint, J=8.0 Hz,2H, CH₂CCH₂) ppm; HRMS (ESI-TOF): calcd. for [C₁₅H₂₂N₄O₁₀Pt—Na⁺]⁺:636.0876, found: 636.0884; elemental analysis calcd. forC₁₆H₂₂N₄O₁₀Pt.H₂O: C: 28.53, H: 3.83, N: 8.87, found: C: 28.62, H: 3.75,N: 8.64.

(OC-6-44)-Acetato[(1R,2R)-cyclohexane-1,2-diamine]oxalato[4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoato]platinum(IV)(22; KP2541)

The compound was synthesized from(OC-6-44)-acetato[(1R,2R)-cyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV)(6; 150 mg, 317.7 μmol) and (isobutyl carbonic)4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoic anhydride (1.5 eq., 140mg, 0.85 mmol) in 2 mL DMF (abs.) according to the general procedure.Purification via preparative RP-HPLC, with a gradient from 15-35%methanol in 20 min, yielded a white solid. Yield: 52.4 mg (26%); ¹H-NMR(DMSO-d6): δ=8.52-8.11 (m, 4H, NH₂), 7.01 (s, 2H, COCH), 3.46-3.36 (m,2H, NCH₂), 2.67-2.51 (m, 2H, CH_(dach)), 2.27 (t, J=7.3 Hz, 2H, COCH₂),2.18-2.06 (m, 2H, CH_(2,dach)), 1.96 (s, 3H, CH₃), 1.68 (quint, J=7.3Hz, 2H, COCH₂CH₂), 1.56-1.35 (m, 4H, CH_(2,dach)), 1.28-1.11 (m, 2H,CH_(2,dach)) ppm; HRMS (ESI-TOF): calcd. for [C₁₈H₂₅N₃O₁₀Pt—Na⁺]⁺:661.1080, found: 661.1080; elemental analysis calcd. forC₁₈H₂₅N₃₁₀Pt.H₂O: C: 32.93, H: 4.15, N: 6.40, found: C: 33.02, H: 4.12,N: 6.33.

Mixture of(OC-6-35-A)-Acetato[(1R,2R,4R)-4-methylcyclohexan-1,2-diamin]oxalato[5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamato]platin(IV)(23) and(OC-6-35-C)-Acetato[(1R,2R,4R)-4-methylcyclohexan-1,2-diamin]oxalato[5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamato]platin(IV)(24)

The compound mixture (KP2552) was synthesized from the racemic mixtureof(OC-6-54-A/C)-acetato[(1R,2R,4R)-4-methylcyclohexane-1,2-diamine]hydroxidooxalatoplatinum(IV)(26/27; 52.0 mg, 106.7 μmol) and1-(5-isocyanatopentyl)-1H-pyrrole-2,5-dione (3 eq., 66.6 mg, 320.1 μmol)in 1.5 mL DMF (abs.) according to the general procedure. Purificationvia preparative RP-HPLC, with a gradient from 18-33% methanol in 30 min,yielded a white solid. Yield: 19.7 mg (27%); 1H-NMR (DMSO-d6): δ=9.62(br, 1H, NH₂), 8.55 (br, 1H, NH₂), 8.25 (br, 2H, NH₂), 7.01 (s, 2H,COCH), 6.78 (br, 1H, NH), 3.41-3.33 (m, 2H, NCH₂), 2.96-2.77 (m, 2H,CH₂), 2.71-2.48 (m, 2H, CH_(2,dach)), 2.16-2.02 (m, 2H, CH_(2,dach)),1.96 (s, 1H, CH₃), 1.57-1.25 (m, 7H, CH_(2,dach), CH₂), 1.25-1.05 (m,3H, CH_(2,dach), CH₂), 1.01-0.84 (m, 1H, CH_(dach)), 0.93 (d, J=6.3 Hz,3H, CH_(3,dach)) ppm; HRMS (ESI-TOF): calcd. for [C₂₁H₃₂N₄O₁₀Pt—Na⁺]⁺:718.1660, found: 718.1661; elemental analysis calcd. forC₂₁H₃₂N₄O₁Pt.0.5H₂O: C: 35.80, H: 4.72, N: 7.95, found: C: 36.11, H:4.68, N: 7.63.

(OC-6-44)-Acetatodiamminedichlorido[5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamato]platinum(IV)(30; KP2540)

The compound was synthesized from(OC-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV) (4; 322 mg,0.86 mmol) and 1-(5-isocyanatopentyl)-1H-pyrrole-2,5-dione (2 eq., 356mg, 1.71 mmol) in 5 mL DMF (abs.) according to the general procedure.Purification via preparative RP-HPLC, isocratic with 25% methanol,yielded a pale yellow solid. Yield: 165.0 mg (33%); ¹H-NMR (DMSO-d6):δ=7.01 (s, 2H, CH), 6.89-6.34 (m, 6H, NH₃), 6.54 (br, 1H, NH), 3.38 (t,J=7.1 Hz, 2H, NCH₂), 2.96-2.80 (m, 2H, NHCH₂), 1.91 (s, 3H, CH₃), 1.47(quint, J=7.3 Hz, 2H, CH₂), 1.41-1.30 (m, 2H, CH₂), 1.24-1.14 (m, 2H,CH₂) ppm; HRMS (ESI-TOF): calcd. for [C₁₂H₂₂Cl₂N₄O₆Pt—Na⁺]⁺: 607.0454,found: 607.0453; elemental analysis calcd. for C₁₂H₂₂Cl₂N₄O₆Pt: C:24.67, H: 3.80, N: 9.59, found: C: 24.58, H: 3.90, N: 9.29.

(OC-6-34)-Acetatodiamminecyclobutane-1,1-dicarboxylato[5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamato]platinum(IV)(31)

The compound was synthesized from(OC-6-44)-acetatodiamminecyclobutane-1,1-dicarboxylatohydroxidoplatinum(IV)(29; 41.0 mg, 101.2 μmol) and1-(5-isocyanatopentyl)-1H-pyrrole-2,5-dione (2 eq., 42.1 mg, 202.3 μmol)in 2 mL DMF (abs.) according to the general procedure. Purification viapreparative RP-HPLC, isocratic with 18% acetonitrile, yielded a whitesolid. Yield: 30.1 mg (51%); 1H-NMR (DMSO-d6): δ=7.07-6.67 (m, 3H, NH₃),6.99 (s, 2H, CH), 6.44-6.00 (m, 3H, NH₃), 6.38 (br, 1H, NH), 3.36 (t,J=7.1 Hz, 2H, NCH₂), 2.96-2.78 (m, 2H, NHCH₂), 2.69-2.54 (m, 3H,CH₂CCH₂), 2.25-2.13 (m, 1H, CH₂CCH₂), 1.94 (s, 3H, CH₃), 1.87-1.73 (m,2H, NCH₂CH₂), 1.51-1.40 (m, 2H, CH₂), 1.39-1.28 (m, 2H, CH₂), 1.23-1.11(m, 2H, CH₂) ppm; ESI-MS: calcd. for [Cl₈H₂₈N₄O₁₀Pt—Na⁺]⁺: 678.13,found: 678.34.

Compounds 21 and 32 to 42 can be prepared in accordance with thesynthesis procedures described in the general part of the presentspecification:

Example 2: RP-HPLC Stability Studies of Compound 12 (KP2299)

The stability of the compounds of the invention in aqueous solutions atdifferent pH values was evaluated by incubation of compound 12 (KP2299)in different buffers and subsequent monitoring of the decrease of thecompound peak area with the UV/VIS detector of a RP-HPLC system at 250nm. Therefore, compound 12 was dissolved at a concentration of 0.5 mM ineither 100 mM phosphate buffer pH=7.4, 100 mM sodium acetate bufferpH=6.3, 100 mM sodium acetate buffer pH=5.3 or 100 mM sodium acetatebuffer pH=4.3 and incubated at 20° C. for 24 hours. All the measurementswere carried out on an Ultimate 3000 RS system (Thermo Scientific,Waltham, Mass., USA) controlled by Chromeleon 7.2 SR4 software using anAcquity BEH C18 reversed phase column (50×3.0 mm, 1.7 μm particle size)from Waters (Milford, USA). Following conditions were used for the runs:flow rate 0.6 mL/min, sampler temperature: 20° C., column oventemperature 25° C., injection volume 10 μL, gradient 5-95% MeOH (and H₂O(+0.1% HCOOH)) in 10 min. The compound was first measured directly afterthe preparation of the compound (after 2-3 min) and thereafter every 60min. The decrease of the compound was calculated by the compound peakareas relatively to the peak area directly after the preparation of thecompound. It was found that the compound is stable at pH=4.3 and pH=5.3without significant changes over 24 h. At pH=6.3 the hydrolysis is below0.5%/h, whereas at pH=7.4 the hydrolysis is quite fast with ˜2.6%/h (seeFIG. 5 ). Corresponding results can be obtained when the furthercompounds of the invention are tested. It has thus been found that thecompounds of the present invention, including KP2299, are particularlystable at a pH of about 4 to 6. Hence, the compounds of formula (I)according to the invention can advantageously be provided in the form ofa liquid aqueous composition having a pH of 4 to 6 (particularly a pH ofabout 5), or as a solid composition for rehydration having a pH of 4 to6 (particularly a pH of about 5) when rehydrated.

Example 3: In Vivo Assays for Anticancer Activity

CT-26 Experiments:

CT-26 colon cancer cells (5×10⁵ in serum-free medium) were injectedsubcutaneously into the right flank of Balb/c mice. Animals were treatedwith the indicated oxaliplatin-releasing drugs at concentrationsequimolar to 9 mg/kg oxaliplatin (i.v.; KP2156, KP2299 (compound 12),and KP2541 (compound 22) were dissolved in 0.9% NaCl solution, KP2260(compound 11) was dissolved in 10% propylene glycol/0.9% NaCl andoxaliplatin was dissolved in 5% glucose solution according to theclinical protocol) twice a week (Mondays and Thursdays). Also in case ofKP2552 (mixture of compounds 23 and 24, with the4-methyl-1,2-cyclohexanediamine moiety) the solvent and applicationscheme of oxaliplatin was used. In case of cisplatin-releasing prodrugsKP2372 (compound 8) and KP2540 (compound 30), a dose equimolar to 3mg/kg cisplatin was applied twice a week. For the carboplatin derivativeKP2551 (compound 20) a dose equimolar to 12 mg/kg carboplatin wasapplied. The complexes were dissolved in 0.9% NaCl, while for theplatinum(II) drugs 5% glucose solution was used according to theclinical protocol. Animals were controlled for distress developmentevery day and tumor size was assessed regularly by caliper measurement.Tumor volume was calculated using the formula: (length×width²).

B16 Experiments:

B16 melanoma cells (1×10⁵ in serum-free medium) were injectedsubcutaneously into the right flank of male C57/B6JRj mice. Animals weretreated with KP2299 at concentrations equimolar to 9 mg/kg oxaliplatin(i.v.; dissolved in 0.9% NaCl solution) twice a week. Oxaliplatin wasdissolved in 5% glucose solution according to the clinical protocol.Animals were controlled for distress development every day and tumorsize was assessed regularly by caliper measurement. Tumor volume wascalculated using the formula: (length×width²).

L1210 Experiments:

L1210 murine leukemia cells (1×10⁵) were injected intraperitoneally in avolume of 0.2 mL into female DBA/2J (cisplatin-releasing drugs) or maleDBA/2J×Balb/c SCID F1 mice (oxaliplatin-releasing drugs). Compounds (seeFIG. 4 ; dissolved as described above) were administeredintraperitoneally at drug concentrations equimolar to 3 mg/kg cisplatinand 9 mg/kg oxaliplatin, respectively, on day 1, 5, and 9. Toxicity wasmonitored by daily observation of animals and registration of their bodyweight. Therapeutic efficacy of the drug candidate was monitored byrecording the lengths of survival of experimental mice compared tountreated control animals.

Results:

One of the mono-functionalized oxaliplatin derivatives (KP2299) revealedexceptionally increased anticancer activity compared to oxaliplatin (seeFIGS. 1A and 2 for CT-26 and FIG. 3 for B16 tumors) and to thebismaleimide compound KP2156 (see FIG. 1B). It is noteworthy that thisactivity was especially pronounced in female mice (see FIG. 2 ), wheretreatment resulted in complete remission in 3 out of 4 animals. This isremarkable as the very similar mono-functionalized analogue KP2260 (seeFIG. 1C), the oxaliplatin-analogue KP2541 which lacks the NH-group inthe linker (see FIGS. 1E and 1F) as well as the4-methyl-1,2-cyclohexanediamine derivative KP2552 were far less or atleast later active than KP2299 (see FIG. 1G). In addition, the cisplatinanalogues KP2372 (see FIG. 1D) and KP2540 were widely inactive (seeFIGS. 1E and 1F). In contrast, the carboplatin prodrug KP2551 had verystrong anticancer activity resulting in complete remissions in 2/4animals. This was especially remarkable as carboplatin in equimolarconcentration had no impact on CT-26 tumor growth at all (see FIG. 1G).

In addition to these promising effects in solid cancer models, also in aleukemia model (L1210) distinctly enhanced anticancer activity resultingin cure of several animals was observed. In contrast, free oxaliplatinresulted only in life prolongation in ˜50% of the treated animals (seeFIG. 4 ). Again, the cisplatin-releasing derivatives did not showeffects superior to free cisplatin. These anti-leukemic effects areunexpected, as maleimide-functionalized drugs are supposed tospecifically target the solid tumor tissue due to the so-called enhancedpermeability and retention effect (EPR effect).

It has thus been demonstrated that the compounds of formula (I)according to the present invention, including in particular thecompounds KP2299 (compound 12) and KP2551 (compound 20), are highlyeffective in the therapy of cancer, including colon cancer, melanoma andleukemia.

The invention claimed is:
 1. A method of treating cancer, wherein thecancer is selected from the group consisting of colon cancer, melanoma,leukemia, ovarian cancer, cervical cancer, lung cancer, small cell lungcancer, non-small cell lung cancer, head and/or neck cancer, head andneck squamous cell carcinoma, breast cancer, and triple-negative breastcancer, the method comprising administering a compound of formula (I) ora pharmaceutically acceptable salt or hydrate thereof to a subject inneed thereof,

wherein: R¹ and R² are joined together to form a moiety (A2) or (A3):

R³ and R⁴ are joined together to form a moiety (B1), or R³ is a moiety(B2) and R⁴ is —NH₃, or R³ and R⁴ are each —NH₃:

R⁵ is —N(R⁵¹)— or —CH₂—; R⁵¹ is hydrogen or C₁₋₈ alkyl; R⁶ is C₁₋₈alkylene, wherein one or two —CH₂— units comprised in said C₁₋₈ alkyleneare each optionally replaced by a group independently selected from thegroup consisting of —O—, —CO—, —C(═O)O—, —O—C(═O)—, —N(R⁶¹)—,—N(R⁶¹)—CO—, —CO—N(R⁶¹)—, arylene, and heteroarylene, wherein saidarylene and said heteroarylene are each optionally substituted with oneor more groups R⁶²; each R⁶¹ is independently selected from the groupconsisting of hydrogen and C₁₋₈ alkyl; each R⁶² is independentlyselected from the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —(C₀₋₃ alkylene)-OH, —(C₀₋₃ alkylene)-O(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SH, —(C₀₋₃ alkylene)-S(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH₂,—(C₀₋₃ alkylene)-NH(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)(C₁₋₈alkyl), —(C₀₋₃ alkylene)-halogen, —(C₀₋₃ alkylene)-(C₁₋₈ haloalkyl),—(C₀₋₃ alkylene)-CF₃, —(C₀₋₃ alkylene)-CN, —(C₀₋₃ alkylene)-CHO, —(C₀₋₃alkylene)-CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-COOH, —(C₀₋₃alkylene)-CO—O—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-O—CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—NH₂, —(C₀₋₃ alkylene)-CO—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—CO—(C₁₋₈alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—NH₂, —(C₀₋₃ alkylene)-SO₂—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—SO₂—(C₁₋₈alkyl), and —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-SO₂—(C₁₋₈ alkyl); R⁷ isselected from the group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,—O—(C₁₋₈ alkyl), —O—(C₂₋₈ alkenyl), —O—(C₂₋₈ alkynyl), —O-cycloalkyl,—O-heterocycloalkyl, —O-aryl, —O-heteroaryl, —N(R⁷¹)—(C₁₋₈ alkyl),—N(R⁷¹)—(C₂₋₈ alkenyl), —N(R⁷¹)—(C₂₋₈ alkynyl), —N(R⁷¹)-cycloalkyl,—N(R⁷¹)-heterocycloalkyl, —N(R⁷¹)-aryl, and —N(R⁷¹)-heteroaryl, whereinsaid C₁₋₈ alkyl or the C₁₋₈ alkyl moiety comprised in any of theaforementioned groups, said C₂₋₈ alkenyl or the C₂₋₈ alkenyl moietycomprised in any of the aforementioned groups, and said C₂₋₈ alkynyl orthe C₂₋₈ alkynyl moiety comprised in any of the aforementioned groupsare each optionally substituted with one or more groups R⁷², and furtherwherein said cycloalkyl or the cycloalkyl moiety comprised in any of theaforementioned groups, said heterocycloalkyl or the heterocycloalkylmoiety comprised in any of the aforementioned groups, said aryl or thearyl moiety comprised in any of the aforementioned groups, and saidheteroaryl or the heteroaryl moiety comprised in any of theaforementioned groups are each optionally substituted with one or moregroups R⁷³; each R⁷¹ is independently selected from the group consistingof hydrogen and C₁₋₈ alkyl; each R⁷² is independently selected from thegroup consisting of —OH, —O(C₁₋₈ alkyl), —SH, —S(C₁₋₈ alkyl), —NH₂,—NH(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl), halogen, C₁₋₈ haloalkyl,—CF₃, —CN, —CHO, —CO—(C₁₋₈ alkyl), —COOH, —CO—O—(C₁₋₈ alkyl),—O—CO—(C₁₋₈ alkyl), —CO—NH₂, —CO—NH(C₁₋₈ alkyl), —CO—N(C₁₋₈ alkyl)(C₁₋₈alkyl), —NH—CO—(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —SO₂—NH₂,—SO₂—NH(C₁₋₈ alkyl), —SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—SO₂—(C₁₋₈alkyl), and —N(C₁₋₈ alkyl)-SO₂—(C₁₋₈ alkyl); each R⁷³ is independentlyselected from the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —(C₀₋₃ alkylene)-OH, —(C₀₋₃ alkylene)-O(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SH, —(C₀₋₃ alkylene)-S(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH₂,—(C₀₋₃ alkylene)-NH(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)(C₁₋₈alkyl), —(C₀₋₃ alkylene)-halogen, —(C₀₋₃ alkylene)-(C₁₋₈ haloalkyl),—(C₀₋₃ alkylene)-CF₃, —(C₀₋₃ alkylene)-CN, —(C₀₋₃ alkylene)-CHO, —(C₀₋₃alkylene)-CO—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-COOH, —(C₀₋₃alkylene)-CO—O—(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-O—CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—NH₂, —(C₀₋₃ alkylene)-CO—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—CO—(C₁₋₈alkyl), —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—NH₂, —(C₀₋₃ alkylene)-SO₂—NH(C₁₋₈ alkyl), —(C₀₋₃alkylene)-SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —(C₀₋₃ alkylene)-NH—SO₂—(C₁₋₈alkyl), and —(C₀₋₃ alkylene)-N(C₁₋₈ alkyl)-SO₂—(C₁₋₈ alkyl); each R⁸ isindependently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, —OH, —O—(C₁₋₈ alkyl), —SH, —S—(C₁₋₈ alkyl), —NH₂,—NH(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl), halogen, C₁₋₈ haloalkyl,—CF₃, —CN, —CHO, —CO—(C₁₋₈ alkyl), —COOH, —CO—O—(C₁₋₈ alkyl),—O—CO—(C₁₋₈ alkyl), —CO—NH₂, —CO—NH(C₁₋₈ alkyl), —CO—N(C₁₋₈ alkyl)(C₁₋₈alkyl), —NH—CO—(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —SO₂—NH₂,—SO₂—NH(C₁₋₈ alkyl), —SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—SO₂—(C₁₋₈alkyl), and —N(C₁₋₈ alkyl)-SO₂—(C₁₋₈ alkyl); each R⁹ is independentlyselected from the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —OH, —O—(C₁₋₈ alkyl), —SH, —S—(C₁₋₈ alkyl), —NH₂, —NH(C₁₋₈alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl), halogen, C₁₋₈ haloalkyl, —CF₃, —CN,—CHO, —CO—(C₁₋₈ alkyl), —COOH, —CO—O—(C₁₋₈ alkyl), —O—CO—(C₁₋₈ alkyl),—CO—NH₂, —CO—NH(C₁₋₈ alkyl), —CO—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—CO—(C₁₋₈alkyl), —N(C₁₋₈ alkyl)-CO—(C₁₋₈ alkyl), —SO₂—NH₂, —SO₂—NH(C₁₋₈ alkyl),—SO₂—N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —NH—SO₂—(C₁₋₈ alkyl), and —N(C₁₋₈alkyl)-SO₂—(C₁₋₈ alkyl); n is an integer of 0 to 8; and m is an integerof 0 to
 6. 2. The method of claim 1, wherein R⁵ is —NH—, —N(—CH₃)— or—N(—CH₂CH₃)—.
 3. The method of claim 1, wherein R⁶ is selected from thegroup consisting of —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, and —(CH₂)₅—.4. The method of claim 1, wherein R⁵ is —NH—, and R⁶ is —(CH₂)₂—.
 5. Themethod of claim 1, wherein R⁷ is C₁₋₅ alkyl.
 6. The method of claim 1,wherein R⁷ is —CH₃.
 7. The method of claim 1, wherein n and m are each0.
 8. The method of claim 1, wherein R³ and R⁴ are joined together toform a moiety (B1), wherein n is 1, and wherein R⁸ is methyl.
 9. Themethod of claim 1, wherein R¹ and R² are joined together to form amoiety (A2), and wherein R³ and R⁴ are joined together to form a moiety(B1).
 10. The method of claim 1, wherein R¹ and R² are joined togetherto form a moiety (A2), and wherein R³ and R⁴ are each —NH₃.
 11. Themethod of claim 1, wherein R¹ and R² are joined together to form amoiety (A3).
 12. The method of claim 1, wherein R¹ and R² are joinedtogether to form a moiety (A2), R³ is a moiety (B2) and R⁴ is —NH₃. 13.The method of claim 1, wherein R¹ and R² are joined together to form amoiety (A2); R⁵ is —NH—, —N(—CH₃)— or —N(—CH₂CH₃)—; R⁶ is selected fromthe group consisting of —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, and—(CH₂)₅—; R⁷ is C₁₋₅ alkyl; and m is
 0. 14. The method of claim 13,wherein R³ and R⁴ are each —NH₃.
 15. The method of claim 1, wherein thecompound of formula (I) is a compound having any one of the followingformulae:

or a pharmaceutically acceptable salt or hydrate thereof.
 16. The methodof claim 1, wherein the compound of formula (I) is a compound having thefollowing formula:

or a pharmaceutically acceptable salt or hydrate thereof.
 17. The methodof claim 13, wherein the compound of formula (I) or hydrate thereof isnot in the form of a salt.
 18. The method of claim 14, wherein thecompound of formula (I) or hydrate thereof is not in the form of a salt.19. The method of claim 15, wherein the compound of formula (I) orhydrate thereof is not in the form of a salt.
 20. The method of claim16, wherein the compound of formula (I) or hydrate thereof is not in theform of a salt.
 21. A method of treating cancer, wherein the cancer isselected from the group consisting of colon cancer, melanoma, leukemia,ovarian cancer, cervical cancer, lung cancer, small cell lung cancer,non-small cell lung cancer, head and/or neck cancer, head and necksquamous cell carcinoma, breast cancer, and triple-negative breastcancer, the method comprising administering a compound having thefollowing formula:

or a hydrate thereof to a subject in need thereof.
 22. The method ofclaim 21, wherein the cancer is colon cancer, melanoma, or leukemia. 23.The method of claim 1, wherein the cancer is colon cancer, melanoma, orleukemia.
 24. The method of claim 1, wherein the method comprisesadministering said compound in combination with an antimitotic agentwhich is selected from the group consisting of paclitaxel,nab-paclitaxel, docetaxel, larotaxel, ortataxel, and tesetaxel.
 25. Themethod of claim 1, wherein the method comprises administering saidcompound in combination with folinic acid and 5-fluorouracil.
 26. Themethod of claim 1, wherein the method comprises administering saidcompound in combination with an immunooncology therapeutic which is ananti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, ananti-TIM3 antibody, an anti-LAG3 antibody, an anti-OX4 antibody, ananti-CSF1R antibody, an anti-IDO antibody, or an anti-CD40 antibody. 27.The method of claim 1, wherein the subject is a human.